Diabetic cardiomyopathy: Mechanisms and new ...

Pharmacology & Therapeutics 142 (2014) 375–415

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Pharmacology & Therapeutics journal homepage: www.elsevier.com/locate/pharmthera

Associate editor: P. Molenaar

Diabetic cardiomyopathy: Mechanisms and new treatment strategies targeting antioxidant signaling pathways Karina Huynh a,b, Bianca C. Bernardo a, Julie R. McMullen a,b,c,⁎,1, Rebecca H. Ritchie a,b,⁎⁎,1 a b c

Baker IDI Heart & Diabetes Institute, Melbourne, Australia Department of Medicine, Monash University, Clayton, Victoria, Australia Department of Physiology, Monash University, Clayton, Victoria, Australia

a r t i c l e

i n f o

Available online 22 January 2014 Keywords: Antioxidants Cardiac remodeling Diabetes Diastolic dysfunction PI3K(p110α) Reactive oxygen species

a b s t r a c t Cardiovascular disease is the primary cause of morbidity and mortality among the diabetic population. Both experimental and clinical evidence suggest that diabetic subjects are predisposed to a distinct cardiomyopathy, independent of concomitant macro- and microvascular disorders. ‘Diabetic cardiomyopathy’ is characterized by early impairments in diastolic function, accompanied by the development of cardiomyocyte hypertrophy, myocardial fibrosis and cardiomyocyte apoptosis. The pathophysiology underlying diabetes-induced cardiac damage is complex and multifactorial, with elevated oxidative stress as a key contributor. We now review the current evidence of molecular disturbances present in the diabetic heart, and their role in the development of diabetes-induced impairments in myocardial function and structure. Our focus incorporates both the contribution of increased reactive oxygen species production and reduced antioxidant defenses to diabetic cardiomyopathy, together with modulation of protein signaling pathways and the emerging role of protein O-GlcNAcylation and miRNA dysregulation in the progression of diabetic heart disease. Lastly, we discuss both conventional and novel therapeutic approaches for the treatment of left ventricular dysfunction in diabetic patients, from inhibition of the renin–angiotensin–aldosterone-system, through recent evidence favoring supplementation of endogenous antioxidants for the treatment of diabetic cardiomyopathy. Novel therapeutic strategies, such as gene

Abbreviations: AAV, adeno-associated virus; ACE, angiotensin converting-enzyme; ACE-I, angiotensin converting-enzyme inhibitor; ACCORD, Action to Control Cardiovascular Risk in Diabetes; AdV, adenovirus; AGE, advanced glycation end product; AMPK, adenosine monophosphate-activated protein kinase; ANBP-2, 2nd Australian National Blood Pressure study; Ang I, angiotensin I; Ang II, angiotensin II; ANP, atrial natriuretic peptide; ARB, angiotensin receptor blocker; AT1, angiotensin II receptor type 1; BH4, tetrahydrobiopterin; BNP, B-type natriuretic peptide; BW, body weight; caPI3K, constitutively active phosphoinositide 3-kinase; CAPPP, Captopril Prevention Project; CONSENSUS, Cooperative North Scandinavian Enalapril Survival Study; CTGF, connective tissue growth factor; CuZnSOD, copper/zinc superoxide dismutase; DAG, diacylglycerol; dnPI3K, dominant negative phosphoinositide 3-kinase; DPP4, dipeptidyl peptidase-4; E/A, ratio of peak early to late (atrial) transmitral blood flow velocities; ECM, extracellular matrix; ecSOD, extracellular superoxide dismutase; eNOS, endothelial nitric oxide synthase; ER, endoplasmic reticulum; ERK, extracellular signal-regulated kinase; ET-1, endothelin-1; FAD, flavin mononucleotide; FADH2, flavin adenine dinucleotide; FAO, fatty acid oxidation; FFA, free fatty acid; FMN, flavin mononucleotide; FPG, fasting plasma glucose; GFAT, glutamine:fructose-6-phosphate amidotransferase; GLP-1, glucagon-like peptide-1; GLUT-4, glucose transporter-4; GPCR, G protein coupled receptor; GPx, glutathione peroxidase; H2O2, hydrogen peroxide; HbA1c, glycated hemoglobin; HBP, hexosamine biosynthesis pathway; HCV, hepatitis C virus; HDL, high density lipoprotein; HF, heart failure; HIF, hypoxia-inducible factor; HMG-CoA, 3-hydroxy-3-methylglutaryl coenzyme A; HOPE, Heart Outcomes Prevention Evaluation; HW, heart weight; HW:BW, heart weight: body weight ratio; IGF-1, insulin-like growth factor-1; IGF-1R, insulin-like growth factor-1 receptor; IL-1β, interleukin-1β; IL-6, interleukin-6; I-R, ischemia–reperfusion; IRS1, insulin receptor substrate 1; IVRT, isovolumic relaxation time; JNK, c-Jun N-terminal kinases; LC3, light chain 3; LDL, low density lipoprotein; LV, left ventricular; LVDP, left ventricular developed pressure; LVEDP, left ventricular end diastolic pressure; LV±dP/dt, peak rate of rise and fall of left ventricular pressure; LVH, left ventricular hypertrophy; LVSP, left ventricular systolic pressure; MAPK, mitogen-activated protein kinase; MEF2C, myocyte enhancer factor-2C; MI, myocardial infarction; MICRO, Microalbuminuria, Cardiovascular and Renal Outcomes; MMP, matrix metalloproteinase; MnSOD, manganese superoxide dismutase; miRNAs, microRNAs; NADH, nicotinamide adenine dinucleotide; NADPH, nicotinamide adenine dinucleotide phosphate; NCX, sodium–calcium exchanger; NEFA, non-esterified fatty acid; NFκB, nuclear factor kappalight-chain-enhancer of activated B cells; NGF, nerve growth factor; NO•, nitric oxide; NOS, nitric oxide synthase; •O2–, superoxide; OGA, β-N-acetylglucosaminidase or “O-GlcNAcase”; O-GlcNAc, O-linked beta-N-acetylglucosamine; OGT, O-GlcNAc transferase; •OH, hydroxyl radical; ONOO–, peroxynitrite; PDTC, pyrrolidine dithiocarbamate; PI3K, phosphoinositide 3-kinase; Pim-1, pro-viral integration site for Moloney murine leukemia virus-1; PKC, protein kinase C; PLB, phospholamban; PPAR-α, peroxisome proliferator-activated receptor alpha; PPAR-γ, peroxisome proliferator-activated receptor gamma; RAAS, renin–angiotensin–aldosterone system; RAGE, receptor for advanced glycation end products; ROS, reactive oxygen species; RyR, ryanodine receptor; SAVE, Survival and Ventricular Enlargement; SECURE, Study to Evaluate Carotid Ultrasound changes in patients treated with vitamin E; SERCA2a, sarcoplasmic reticulum Ca2+ ATPase; SGK1, serum and glucocorticoid-regulated kinase 1; siRNA, small interfering RNA; SOD, superoxide dismutase; SOLVD, Studies of Left Ventricular Dysfunction; SR, sarcoplasmic reticulum; STZ, streptozotocin; T1DM, type 1 diabetes mellitus; T2DM, type 2 diabetes mellitus; TGF-β, transforming growth factor-β; TIMP, tissue inhibitor of metalloproteinase; TNF-α, tumor necrosis factor-alpha; TRACE, Trandolapril Cardiac Evaluation; Trx, thioredoxin; TxNIP, thioredoxin-interacting protein; TZD, thiazolidinediones; UDPGlcNAc, UDP-N-acetylglucosamine; UKPDS, UK Prospective Diabetes Study; VADT, Veterans Affairs Diabetes Trial. ⁎ Correspondence to: J.R. McMullen, Head, Cardiac Hypertrophy, Baker IDI Heart & Diabetes Institute, PO Box 6492, St Kilda Rd Central, Melbourne, VIC 8008, Australia. Tel.: +61 3 8532 1194; fax: +61 3 8532 1100. ⁎⁎ Correspondence to: R.H. Ritchie, Head, Heart Failure Pharmacology, Baker IDI Heart & Diabetes Institute, PO Box 6492, St Kilda Rd Central, Melbourne, VIC 8008, Australia. Tel.: +61 3 8532 1392; fax: +61 3 8532 1100. E-mail addresses: [email protected] (J.R. McMullen), [email protected] (R.H. Ritchie). 1 Both authors contributed equally to this work. 0163-7258/$ – see front matter © 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.pharmthera.2014.01.003

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therapy targeting the phosphoinositide 3-kinase PI3K(p110α) signaling pathway, and miRNA dysregulation, are also reviewed. Targeting redox stress and protective protein signaling pathways may represent a future strategy for combating the ever-increasing incidence of heart failure in the diabetic population. © 2014 Elsevier Inc. All rights reserved.

Contents 1. Diabetic cardiomyopathy . . . . . . . . . . . . . . . . . . . . . . . . . 2. Disturbances in the diabetic heart . . . . . . . . . . . . . . . . . . . . . 3. Signaling pathways implicated in diabetic cardiomyopathy . . . . . . . . . 4. Conventional therapies for treatment of diabetic cardiomyopathy . . . . . . 5. Early evidence favoring antioxidants for treatment of diabetic cardiomyopathy 6. Novel therapies offering new promise for diabetic cardiomyopathy . . . . . . 7. Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conflict of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1. Diabetic cardiomyopathy 1.1. Introduction and overview of type 1 and type 2 diabetes Diabetes mellitus is firmly established as a major threat to human health in the 21st century due to its alarming rise in incidence over the past two decades, which has attracted considerable attention. This rise in incidence is largely attributed to environmental and lifestyle changes, where increased occurrence of obesity is accompanied by an increasing number of people diagnosed with diabetes mellitus (Zimmet et al., 2001). An estimated 285 million adults globally were burdened by this chronic disease in 2010; this number is projected to increase to 439 million by 2030 (Shaw et al., 2010). Diabetes is regarded as the 5th leading cause of death worldwide, following infectious diseases, cardiovascular disease, cancer and trauma (Roglic et al., 2005). The rise in incidence and prevalence of diabetes also imposes a significant economic burden globally, particularly in developed countries, with an estimated 12% of the worldwide health care expenditure spent on the treatment and prevention of diabetes (Farag & Gaballa, 2011). Diabetes is a chronic, progressive metabolic disorder characterized by insulin deficiency and/or resistance, resulting in elevated plasma glucose levels. There are two predominant types of diabetes; type 1 diabetes mellitus (T1DM), formerly known as insulin-dependent or juvenile diabetes and type 2 diabetes mellitus (T2DM), otherwise known as non-insulin-dependent or adult-onset diabetes. T1DM, which accounts for approximately 5–10% of all cases of diabetes (Raskin & Mohan, 2010), has a steadily increasing incidence worldwide (Karvonen et al., 2000). Auto-immune mechanisms (at least in genetically-predisposed individuals) and/or environmental risk factors are regarded as key triggers of T1DM (Zimmet et al., 2001; Di Lorenzo et al., 2007). T2DM, characterized by insulin resistance, accounts for the remaining ~90% of all cases of diabetes, and occurs predominantly, but not exclusively, in the older population (Zimmet et al., 2001). The global rate of mortality attributable to T2DM has been estimated at 2.9 million, or 5.2% of all deaths (Roglic et al., 2005; Nolan et al., 2011). In contrast to developed countries (where T2DM is most evident in individuals over 60 years of age), people aged 40–60 years old comprise the majority of T2DM cases in developing countries (Shaw et al., 2010), thus likely to impact on productivity in those of working age. The rising incidence of T2DM is strongly associated with environmental factors such as obesity and sedentary lifestyle (Zimmet et al., 2001) that accompany an increasingly ‘westernizeddiet’, higher in fat, sugar and energy density (Astrup et al., 2008). Genetic factors such as family history of diabetes and ethnic background are also important for the development of the disease (Nolan et al., 2011). Insulin

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resistance is the primary metabolic abnormality among T2DM patients, resulting in both hyperglycemia and hyperinsulinemia. Pancreatic β-islet cell dysfunction is also implicated in the progression of T2DM (Kahn, 2003; Muoio & Newgard, 2008). Glucotoxicity and lipotoxicity may further impair and reduce the rate of insulin secretion from dysfunctional β-islet cells (Nolan et al., 2011). 1.2. Microvascular and macrovascular complications of diabetes mellitus As has been widely reviewed, both T1DM and T2DM are associated with increased risk of macrovascular and microvascular complications (Williams et al., 2002; Forbes & Cooper, 2013). These vascular injuries often coexist and can result in hypertension, altered vascular permeability and ischemia (Krentz et al., 2007; Calcutt et al., 2009). Common microvasculature defects evident in diabetes include retinopathy, nephropathy and peripheral neuropathy, each of which can impart debilitating consequences. Diabetic retinopathy can lead to blindness (Cheung & Wong, 2008), diabetic nephropathy can result in end-stage renal failure (Calcutt et al., 2009) and diabetic neuropathy can progress to peripheral nerve dysfunction in distal regions such as the hands and feet (Bansal et al., 2006). Diabetic retinopathy also serves as a marker of generalized hyperglycemic damage in the microvasculature (Cheung & Wong, 2008). In addition to these widespread defects in the diabetic systemic microvasculature, macrovascular complications such as coronary heart disease, stroke and peripheral vascular disease are thought to be the primary causes of morbidity and mortality in diabetic patients (Williams et al., 2002; Forbes & Cooper, 2013). Increased plaque formation, atherosclerosis progression and vasodilator/ vasoconstrictor dysregulation are evident in larger arteries (Vinik & Flemmer, 2002), as well as impairments at the level of platelet function (hyperaggregability, reduced fibrinolysis, etc.) and alterations in blood flow. The combination of all of these vascular defects contributes to the high incidence of cardiovascular disease, cerebrovascular disease (including stroke) and peripheral arterial disease in diabetes (Cade, 2008). Independent of the macrovascular complications of the disease, both clinical and experimental studies have highlighted the existence of a specific diabetic cardiomyopathy, in which alterations at the level of the cardiomyocyte are evident (Davidoff et al., 2004). Rubler et al. first described diabetic cardiomyopathy as a distinct entity 40 years ago, in a small cohort of diabetic patients with adverse myocardial structural changes at post-mortem, in the absence of coronary arterial disease, hypertension or valvular complications (Rubler et al., 1972). Considerable attention was dedicated to identifying and characterizing this distinct cardiomyopathy in the following four decades, thus profoundly increasing

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the awareness of diabetes as a risk factor for heart failure (HF). The Framingham Heart study established early epidemiological links between diabetes and increased risk of HF (Kannel et al., 1974). When compared to age-matched control subjects, the relative risk of developing HF is 2-fold greater in diabetic males, and 5-fold greater in diabetic females, independent of age, obesity, dyslipidemia and coronary heart disease. More recent retrospective analysis suggests that diabetes not only escalates the risk of HF, but also increases its incidence N2.5-fold (Nichols et al., 2004; Thrainsdottir et al., 2005; Aksnes et al., 2007). Prevalence of HF continues to increase with age; for every elderly diabetic person free of HF, approximately 12 will develop HF over the ensuing year, with 6 mortalities (Bertoni et al., 2004). As a result, diabetic patients account for 15% to 35% of patients in HF clinical trials (Cohen-Solal et al., 2008), and diabetes is an independent predictor of poor outcome in HF, as demonstrated in several trials, including SOLVD (Studies of Left Ventricular Dysfunction) (Shindler et al., 1996; Domanski et al., 2003; Pocock et al., 2006). This strong association between diabetes and HF is further supported by evidence from experimental models, where diabetes induces cardiac structural, metabolic and functional change (Joffe et al., 1999; Greer et al., 2006; Yue et al., 2007). Although these large epidemiological studies reveal the important impact of diabetes per se on heart failure risk, underlying coronary artery disease is a common comorbidity in diabetic patients. Both the risk of development and the severity of ischaemic heart disease are increased in diabetic patients relative to their non-diabetic counterparts (Rytter et al., 1985; Stevens et al., 2004). The net marked myocardial dysfunction in the diabetic patient thus likely reflects both increased coronary heart disease (secondary to atherosclerosis) as well as the specific diabetic cardiomyopathy (Rubler et al., 1972; Devereux et al., 2000; Marwick, 2008; Boudina & Abel, 2010). HF presents earlier in diabetic patients, with heart failure prevalence increased 5- to 8-fold in the 45–65-year-old age group (Devereux et al., 2000; Gilbert et al., 2006). Despite this added burden that diabetes poses on the heart, current therapeutic strategies do not specifically address diabetes-induced heart failure. Clinical management of heart failure in affected patients is managed similarly regardless of whether there is coexistent diabetes. These disturbances that characterize diabetic cardiomyopathy likely contribute to the high incidence of cardiac mortality in diabetic patients (Galderisi et al., 1991; Devereux et al., 2000; Vinereanu et al., 2003). Therefore, the mechanisms underlying the development of diabetic cardiomyopathy warrant urgent and detailed investigation, in order to improve disease management strategies and reduce morbidity and mortality rates in affected patients. 1.3. Features of the diabetic heart It is widely accepted that the diabetic heart is associated with left ventricular (LV) diastolic (and often systolic) dysfunction, cardiomyocyte hypertrophy, myocardial interstitial fibrosis, increased apoptosis and upregulation of oxidative stress (Fig. 1). The pathophysiology of diabetic cardiomyopathy is thus complex and multifactorial (Hahn et al., 2003; McQueen et al., 2005; Connelly et al., 2007; Palmieri et al., 2008), as described in detail below. 1.3.1. Diastolic dysfunction LV diastolic dysfunction is one of the first signs of diabetic cardiomyopathy, often developing before systolic dysfunction (Schannwell et al., 2002; Diamant et al., 2003; Palmieri et al., 2008). The prevalence of diastolic HF (also known as HF with preserved ejection fraction) is continually rising. It is estimated to account for one third to one half of all HF occurrences (Colucci & Braunwald, 1997; Little & Braunwald, 1997; Bajraktari et al., 2006; Cohen-Solal et al., 2008), with similar prognosis as systolic HF (Bhatia et al., 2006; Owan et al., 2006). Diastolic dysfunction is an integral characteristic of heart failure with preserved ejection fraction (HFPEF) or diastolic heart failure, in which other impairments such as concentric hypertrophy and vascular stiffness are likely to also

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Features of the diabetic heart (common to both type 1 and type 2 diabetes)

Non-diabetic

Diastolic dysfunction (↓E/A ratio)

Diabetic

E A

Cardiomyocyte hypertrophy

Myocardial fibrosis

↑ Apoptosis

↑ ROS generation (DHE fluorescence)

Fig. 1. Overview of the features of the diabetic heart. The diabetic heart is characterized by early diastolic dysfunction (shown here as a reduction in the E/A wave ratio, derived from Doppler echocardiography), an increase in cardiomyocyte hypertrophy (shown here as an increase in cardiomyocyte size on hemotoxylin and eosin staining), increased cardiac fibrosis (collagen appears red, on Sirius red staining), elevated apoptosis (positivelystained apoptotic cells appear blue, on TUNEL staining, with three examples indicated by arrows) and elevated ROS generation (as indicated by enhanced dihydroethidium (DHE) fluorescence on reactivity with superoxide). This cardiac phenotype is similar in type 1 and type 2 diabetes (Huynh et al., 2012; Huynh et al., 2013). As diastolic dysfunction progresses however the E/A ratio may manifest as a pseudonormal pattern, prior to subsequent development of a restrictive pattern on Doppler echocardiography (as detailed in Gilbert et al., 2006). Use of other imaging modalities such as Tissue Doppler permits assessment of diastolic function on more load-independent measures, e.g. via E/E’.

manifest (Alagiakrishnan et al., 2013; Paulus & Tschope, 2013). As recently reviewed by Wood et al., systolic and diastolic dysfunction can result in differences in gross cardiac morphology, associated for example with a dilated ventricle versus an absence of chamber dilation, respectively (Wood et al., 2011). There remains a debate regarding the existence of isolated diastolic dysfunction as an indicator of diabetic cardiomyopathy, as patients in the early stages of diabetes do not routinely receive evaluation of diastolic function. Furthermore, the cardiac complications of diabetes are usually investigated only after overt symptoms are evident. LV diastolic dysfunction, characterized by impaired and prolonged isovolumetric ventricular relaxation time (IVRT) (Satpathy et al., 2006), can be reliably detected using imaging techniques such as Doppler echocardiography, tissue Doppler and magnetic resonance imaging

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(Nishimura et al., 1989; Galderisi et al., 1991; Yu et al., 2007). Doppler echocardiography measures peak blood flow velocity across the mitral valve, to permit regional assessment of myocardial filling, using the ratio of the peak initial (E, early) and second (A, or atrial) blood flow velocity across the mitral valve (Fig. 1). A reduced E/A ratio coupled with prolonged IVRT, indicative of diastolic dysfunction, is commonly observed in diabetic patients (Zarich et al., 1988; Schannwell et al., 2002; Fang et al., 2003). Doppler echocardiography is commonly used as a non-invasive technique for the assessment of diastolic function (Nishimura et al., 1989) in both T1DM (Schannwell et al., 2002) and T2DM settings. This technique has been used to demonstrate that impairments in LV relaxation are evident in at least half of asymptomatic diabetic subjects without overt cardiovascular disease or microvascular complications (Zarich et al., 1988; Zabalgoitia et al., 2001). In contrast, pulse-wave tissue Doppler imaging measures the movement of a particular segment of cardiac muscle tissue relative to the sensor. Diastolic early (E’, to distinguish it from conventional transmitral E flow) and late (A’, as distinct from conventional transmitral A flow) myocardial tissue velocities are derived by integrating these distances over time. LV filling pressure can also be estimated from tissue Doppler imaging, as the ratio of conventional early (E) transmitral flow velocity to diastolic early (E’) tissue velocity (E/E’). This technique has been used to demonstrate that LV filling (on E/E’) is impaired in patients with T2DM (Belke et al., 2000; Vinereanu et al., 2003; Yu et al., 2007), independent of LV mass, systolic function or microvascular complications. Cardiac magnetic resonance imaging has now emerged as another non-invasive technique for the measurement of cardiac function by providing a 3-dimensional representation of the structure of the heart. This technique yields the same indices of diastolic function as Doppler echocardiography (E/A, deceleration time, LV filling pressures), but with increased sensitivity and reproducibility. In asymptomatic patients with T2DM, cardiac magnetic resonance detected impairments in diastolic function, including reductions in reduced LV end-diastolic volume, E and E/A (Rijzewijk et al., 2009). Importantly, as conventional echocardiography-derived measures of diastolic function such as E/A are heavily dependent on preload, load-independent measures such as E/E’ derived from tissue Doppler more reliably describe the status of diastolic dysfunction, particularly in the latter stages of the disease (see Gilbert et al., 2006). Diastolic dysfunction has been similarly well characterized in various rodent experimental models of T1DM and T2DM (described at Section 1.4). Streptozotocin (STZ)-induced T1DM rats and mice exhibited impairments in diastolic function, as shown on Doppler echocardiography (E/A, deceleration time, and IVRT, Fig. 1) and cardiac catheterization (elevated LV end-diastolic pressure, LVEDP) in vivo (Hoit et al., 1999; Joffe et al., 1999; Wang et al., 2006; Lacombe et al., 2007; Shao et al., 2007; Huynh et al., 2010; Ritchie et al., 2012; Huynh et al., 2013). Similar evidence has been obtained using Doppler echocardiography and cardiac catheterization in rodent models of T2DM, including the db/db mouse and sucrose-fed rat (Mizushige et al., 2000; Semeniuk et al., 2002; Vasanji et al., 2006; Connelly et al., 2007; Huynh et al., 2012). Together, these various imaging techniques provide a powerful means for the early detection of diabetes-induced diastolic dysfunction in both clinical and experimental settings. Diabetic cardiomyopathy, as a distinct entity from associated microvascular diseases, is evident even in individual cardiomyocytes (Ren & Davidoff, 1997; Davidoff et al., 2004; Fulop et al., 2007b). Isolated LV diastolic dysfunction likely represents its initial stage of progression, although the mechanisms underlying this remain to be fully resolved. Likely contributors include insulin resistance (Bajraktari et al., 2006), increased cardiac collagen deposition (Mizushige et al., 2000; van Heerebeek et al., 2008), alterations in both glucose metabolism (Belke et al., 2000), generation of reactive oxygen species (ROS) (Huynh et al., 2012; Ritchie et al., 2012; Huynh et al., 2013) and Ca2+ homeostasis (Davidoff et al., 2004; Fulop et al., 2007b), as discussed in detail below.

1.3.2. Systolic dysfunction The majority of evidence regarding diabetic cardiomyopathy considers LV diastolic dysfunction to largely occur in isolation, or prior to LV systolic dysfunction, as outlined above. A smaller number of studies have however suggested that abnormal systolic function may also be evident, in both clinical (Yu et al., 2002; Vinereanu et al., 2003) and experimental settings (Semeniuk et al., 2002; Wichi et al., 2007; Yu et al., 2007). Subclinical systolic dysfunction has been demonstrated in patients with T2DM, who exhibit regional impairments in LV systolic function, on both longitudinal and radial systolic velocities despite normal ejection fraction, peak systolic velocity and functional reserve (Vinereanu et al., 2003). The development of systolic dysfunction in experimental diabetic settings may be model-dependent; systolic function is preserved in STZ-induced T1DM mice when using multiple low doses of STZ on the FVB/N strain (Huynh et al., 2010; Ritchie et al., 2012; Huynh et al., 2013), yet STZ in C57Bl/6 mice can decrease stroke volume, cardiac output, LV ejection fraction and fractional shortening (Westermann et al., 2007). 1.3.3. Cardiomyocyte hypertrophy The functional alterations evident in the diabetic heart are closely associated with molecular and histopathological evidence of both cardiomyocyte hypertrophy and fibrosis (Fig. 1). LV hypertrophy is a common structural hallmark in patients with diabetes, and is of clinical significance as it is a strong predictor of myocardial infarction (MI), stroke and death from HF (Bernardo et al., 2010). The development of LV hypertrophy initially occurs as an adaptive response to elevated hemodynamic stress (Ritchie et al., 2009), reduced numbers of functional contractile cardiomyocytes (van Empel & De Windt, 2004) and neurohormonal activation (Eguchi et al., 2008). Although LV hypertrophy is frequently associated with increased afterload in diabetic patients with hypertension (Bell, 2008), it can also occur independent of pressure-overload (Galderisi et al., 1991; Eguchi et al., 2008; Huynh et al., 2010). Echocardiographic evidence revealed increased LV posterior wall thickness and mass, in addition to a greater ratio of wall thickness to chamber radius in diabetic patients, even in the absence of coronary artery disease or hypertension (Eguchi et al., 2008). The risk of elevated LV mass in patients with diabetes was increased in the order of 1.5-fold, independent of body mass. Similar evidence of diabetes-induced hypertrophy has been obtained from animal studies, with increases in heart-tobody weight ratio (HW/BW) and cardiomyocyte size and/or upregulated hypertrophic gene expression (e.g. β-myosin heavy chain, atrial natriuretic peptide, ANP; B-type natriuretic peptide, BNP), often in the absence of hypertension (Candido et al., 2003; Chang et al., 2006; Connelly et al., 2007; Ritchie et al., 2007; Huynh et al., 2010; Ritchie et al., 2012; Huynh et al., 2013). 1.3.4. Myocardial fibrosis Another structural hallmark of the diabetic myocardium is the development of interstitial and/or perivascular fibrosis. Extracellular matrix (ECM) is composed of collagen, elastin, laminin and fibronectin, which normally provide a scaffold for cardiomyocytes. Collagen is an integral component of the ECM, as it facilitates connections between cells and muscle bundles, maintaining myocardial structure, shape and chamber thickness (Shimizu et al., 1993; Daniels et al., 2009). Myocardial fibrosis is a result of abnormally elevated ECM deposition, in particular collagen, which increases myocardial stiffness. This impairs LV relaxation, with subsequent compromise in the efficiency of LV contraction. In the diabetic setting, a decrease in the activity of ECMdegrading enzymes, matrix metalloproteinases (MMP), coupled with an increase in activity of their tissue inhibitors (TIMP) has been proposed as a mechanism underlying ECM accumulation (Westermann et al., 2007; Van Linthout et al., 2008). Furthermore, diabetes increases the proportion of collagen that is in the insoluble form (Shimizu et al., 1993). Elevated myocardial content and gene expression of ECM

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proteins (particularly collagen) is often observed in experimental models of both T1DM (Candido et al., 2003; Yoon et al., 2005; Connelly et al., 2007; Westermann et al., 2007; Huynh et al., 2010; Ritchie et al., 2012) and T2DM (Mizushige et al., 2000; Ritchie et al., 2007; Ritchie et al., 2013), and is closely associated with impairments in LV diastolic filling. As reviewed by Asbun & Villarreal (Asbun & Villarreal, 2006), collagen type I and III are increased in the epicardial and perivascular regions of the human diabetic heart, whereas the endocardium accumulated collagen type IV. Diabetes-induced cardiac fibrosis is accompanied (and likely triggered) by the upregulation of transforming growth factor (TGF-β1), its receptor TGF-β receptor II, and its downstream mediator, connective tissue growth factor (CTGF) (Mizushige et al., 2000; Way et al., 2002; Westermann et al., 2007; D'Souza et al., 2011). Perhaps not surprisingly, alterations in glucose metabolism are an important contributing mechanism to diabetesinduced cardiac remodeling. Hyperglycemia per se is sufficient to directly increase cardiac fibroblast and vascular smooth muscle cell proliferation (Begum & Ragolia, 2000; Tokudome et al., 2004), in addition to elevating pro-growth signaling in cultured cardiomyocytes (Wen et al., 2005). 1.3.5. Apoptosis and/or autophagy Defective governing of programmed cell death is implicated in several cardiac pathologies, including diabetes. Apoptosis is the most well-known form of programmed cell death; tightly-controlled regulation of apoptosis is essential for maintaining tissue homeostasis under normal physiology (Frustaci et al., 2000; Lee & Pervaiz, 2007). Apoptotic pancreatic β-islet cell death is a likely causal factor in both T1DM and T2DM (Leonardi et al., 2003; Lee & Pervaiz, 2007). Increased myocyte apoptosis is involved in the process of transition from the compensated to decompensated hypertrophic state in the diabetic heart (Frustaci et al., 2000). Cardiomyocyte apoptosis is correlated with blood glucose levels (Fiordaliso et al., 2000). Overwhelming evidence from both clinical and experimental settings now indicates that cardiomyocyte apoptosis (Fig. 1) also plays an important causal role in the development of diabetic cardiomyopathy (Fiordaliso et al., 2000; Frustaci et al., 2000; Cai et al., 2002; Kuethe et al., 2007; Ritchie et al., 2012; Huynh et al., 2013). Diabetes-induced cardiomyocyte apoptosis often occurs concomitantly with other structural anomalies including increased interstitial fibrosis (Ritchie et al., 2012; Huynh et al., 2013) and myofiber disarray (Frustaci et al., 2000; Yoon et al., 2005), and is likely to be a direct result of hyperglycemia-triggered caspase-3 activation (Cai et al., 2002). Recently, considerable attention has been paid to an alternate form of programmed cell death, autophagy, which under normal physiology is a protective mechanism to remove unwanted cells, damaged proteins or defective organelles (Ebato et al., 2008; Eskelinen & Saftig, 2009; Masini et al., 2009; Gottlieb & Mentzer, 2010; Rifki & Hill, 2012; Yamaguchi et al., 2012). As recently reviewed by Yamaguchi et al. (Yamaguchi et al., 2012), autophagy entails the compartmentalization into double-membrane vacuoles of redundant cell constituents that have been earmarked for degradation and elimination, prior to vacuole–lysosome fusion. Common markers of autophagy include microtubule-associated protein light chain 3 (LC3) puncta, doublemembrane vesicles on electron microscopy, autophagic flux, the ratio of the active LC3-II isoform to the inactive LC3-I isoform, as well as gene expression or protein levels of autophagy-related genes Atg5, Atg7, Beclin-1 and the LC3-binding protein p62 (Ebato et al., 2008; Eskelinen & Saftig, 2009; Masini et al., 2009; Mellor et al., 2011; Rifki & Hill, 2012; Yamaguchi et al., 2012). Usually if three of these markers are upregulated, one can cautiously be confident that autophagy is present. Autophagy is increasingly recognized as an important cell survival mechanism, as it regulates the turnover of long-lived proteins and protects cells during periods of starvation and other cell stressors (Ebato et al., 2008; Eskelinen & Saftig, 2009; Gottlieb & Mentzer, 2010; Rifki & Hill, 2012; Yamaguchi et al., 2012).

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However, dysregulated autophagy may result in excessive cell death, as has been implicated in various diseases including cancer, neurodegenerative disorders, and more recently, diabetes (Ebato et al., 2008; Eskelinen & Saftig, 2009; Mellor et al., 2011). For example, the density of autophagic vacuoles (indicative of aberrant autophagy) in pancreatic β-islet cells is increased in insulin-resistance and diabetes (Ebato et al., 2008; Masini et al., 2009). Whether autophagy is beneficial or detrimental in the heart remains controversial at present, with conflicting views surrounding excessive versus insufficient autophagy in the pathophysiology of cardiac dysfunction and cardiomyocyte death (Gottlieb & Mentzer, 2010; Rifki & Hill, 2012; Yamaguchi et al., 2012). Fructose-fed, insulin-resistant mice exhibited selective increases in autophagic (but not apoptotic) cardiomyocyte signaling, accompanied by upregulated cardiac superoxide production and fibrosis (Mellor et al., 2011). In contrast, reduced cardiomyocyte autophagy is observed in diabetic OVE26 mice, in parallel with cardiac dysfunction and reduced adenosine monophosphateactivated protein kinase (AMPK) activity (Xie et al., 2011). Altered regulation of various components of autophagic signaling in the diabetic heart may thus be a compensatory response to protect cells under conditions of cardiac stress. The contribution of this altered autophagic response to the pathogenesis of diabetic cardiomyopathy however requires further elucidation. Given the importance of normal autophagic processes in preserving normal cardiac function and morphology, therapeutic strategies directed at multiple cell death pathways may be necessary for the prevention and treatment of diabetes-induced cardiac dysfunction. 1.3.6. Microvascular abnormalities Although the debilitating characteristics of diabetic cardiomyopathy can develop independent of the macrovascular complications of the disease, structural and functional changes at the level of the coronary vasculature are a common co-morbidity in diabetic patients, which can further aggravate diabetic cardiomyopathy. Sustained hyperglycemia is associated with endothelial dysfunction (Farhangkhoee et al., 2006; Woodman et al., 2008). As a result, the risk of enhanced microvascular permeability, impaired microvascular blood flow and subsequent tissue ischemia is increased (Di Carli et al., 2003; Oltman et al., 2006). This process is exacerbated by changes in the expression and bioavailability of vasoactive factors released from the endothelium, including upregulation of endothelin-1 (ET-1) and downregulation of nitric oxide (NO•) (Mather et al., 2004; Farhangkhoee et al., 2006). Endothelial-derived NO• is a potent endogenous vasodilator and negative regulator of abnormal cardiomyocyte growth (Irvine et al., 2008; Luksha et al., 2009; Ritchie et al., 2009; Leo et al., 2011). Numerous studies have reported the diabetes-induced impairment in endothelium-dependent vasodilatation (Hogikyan et al., 1998; Hink et al., 2001; van de Ree et al., 2001; Edgley et al., 2008; Woodman et al., 2008), reduced capillary density and impaired coronary microvascular perfusion (Chou et al., 2002; Yoon et al., 2005), which have implications for the susceptibility of the diabetic heart to ischemic damage (Farhangkhoee et al., 2006). Therapeutic approaches targeting impairments at the level of the coronary microvasculature may thus offer favorable benefits in the setting of diabetic cardiomyopathy. Autonomic neuropathy may also impact on diabetic cardiomyopathy, as recently reviewed in detail elsewhere (Stables et al., 2013; Vinik et al., 2013; Voulgari et al., 2013). 1.4. Animal models of diabetic cardiomyopathy Animal models are indispensable as a research tool for increasing our understanding of underlying mechanisms implicated in diabetic cardiomyopathy. Rodent models are relatively resistant to developing atherosclerosis, thus effectively allowing for the study of changes within the diabetic heart independent of coronary artery disease (Bugger & Abel, 2009). Cardiac research over the recent years has seen an

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increasing trend to utilize murine models due to ease of maintenance, short breeding cycles and the high homology of the human and mouse genome (Waterston et al., 2002). Mouse models are favored in particular for the study of diabetic cardiomyopathy, due to the ease of generating transgenic models expressing specific gain-of-function and loss-of-function mutations, as well as the overexpression or deletion of specific genes to rescue or exacerbate disease. Despite the plethora of knowledge acquired from such studies, the efficacy of using rodents to model diabetic heart disease has been questioned. Whether murine cardiac physiology can replicate the facets of human cardiac physiology has been disputed, in the light of differential traits such as shorter cardiac cycle lengths and differences in the expression of electrophysiological and contractile protein isoforms (James et al., 1998). Despite this, there are many similar characteristics between human diabetic cardiomyopathy and rodent models. Commonly used type 1 diabetic rodent models include the STZ mouse/rat, the OVE26 mouse, BioBreeding Wistar rat, and the Akita mouse. Rodent models of T2DM include the spontaneous ob/ob and db/db mouse, the Zucker fatty rat and Zucker diabetic fatty rat, as well as both diet-induced and knock-out models of insulin resistance. The use of these animal models for diabetic cardiomyopathy has been extensively reviewed by Bugger and Abel (Bugger & Abel, 2009), and Hsueh et al. (Hsueh et al., 2007). Table 1 provides a short summary of the cardiac phenotypes of each of the common animal models of diabetes. 2. Disturbances in the diabetic heart 2.1. Pathophysiologic triggers of diabetic cardiomyopathy 2.1.1. Hyperglycemia Hyperglycemia represents one of the central drivers of the metabolic, functional and structural alterations present in the diabetic heart. Aberrations in glucose control itself is sufficient to trigger an array of maladaptive processes including hyperinsulinemia and insulin resistance (Shanik et al., 2008), glucose transporter-4 (GLUT-4) depletion (Garvey et al., 1991), changes in free fatty acid (FFA) oxidation (Kelley & Simoneau, 1994; Robertson et al., 2004), accumulation of advanced glycation end products (AGEs) (Goh & Cooper, 2008; Yao & Brownlee, 2010), altered Ca2+ handing (Ligeti et al., 2006), increased generation of ROS (Fiordaliso et al., 2004; Yao & Brownlee, 2010) and activation of the renin–angiotensin–aldosterone system (RAAS) (Giacchetti et al., 2005; Lavrentyev et al., 2007; Putnam et al., 2012). All of these mechanisms have been implicated in the development and progression of diabetic cardiomyopathy (Fang et al., 2004), as discussed later. Several clinical studies have demonstrated a clear correlation between glycemic control and the risk of HF development and associated events, on both fasting plasma glucose (FPG) and glycated hemoglobin (HbA1c) levels (Turner et al., 1998; Iribarren et al., 2001; Held et al., 2007). Further, uncontrolled hyperglycemia in T2DM patients without overt cardiomyopathy is associated with diastolic LV dysfunction, independent of obesity, dyslipidemia and systemic arterial hypertension (Sanchez-Barriga et al., 2001). Together, these studies emphasize the importance of effective glycemic control in the prevention of cardiovascular events in diabetic patients. 2.1.2. Insulin resistance Insulin resistance, and the usually-concomitant hyperinsulinemia, are significant risk factors for the development and progression of cardiovascular disease. Evidence exists to indicate a causal relationship between hyperinsulinemia, hypertension and coronary artery disease (Bianchi et al., 1994; Lender et al., 1997; Sun & Ernsberger, 2007). Untreated essential hypertension is linked to higher fasting and postprandial insulin levels and impaired insulin sensitivity in both hypertensive patients and in animal models with a genetic predisposition to hypertension (Bianchi et al., 1994; Lender et al., 1997; Sun & Ernsberger, 2007). Activation of the sympathetic nervous system is one mechanism

considered to underlie the development of high blood pressure under insulin-resistant settings (Reaven et al., 1996); renal sodium retention and increased proliferation of vascular smooth muscle cells may also contribute. Hyperinsulinemia is positively correlated with the risk of developing coronary artery disease, as demonstrated by a number of studies (Pyöräla, 1979; Fontbonne et al., 1991; Eddy et al., 2009). The incidence of coronary artery disease associated with high triglycerides and low high-density lipoprotein levels is only significantly increased when accompanied by insulin resistance, even in the absence of diabetes (Robins et al., 2011). Furthermore, impaired insulin sensitivity can be detected even in well-managed T2DM patients free of coexistent comorbidities (Bonora et al., 2002). Cardiac abnormalities, including LV hypertrophy, fibrosis and cardiomyocyte dysfunction are often already apparent in the prediabetic, insulin-resistant stage, as observed in animal models in vivo (Dutta et al., 2001; D'Souza et al., 2011; Ritchie et al., 2013). Although much attention has been devoted to elucidating the mechanisms underlying peripheral insulin resistance, whether these mechanisms are also responsible for cardiac insulin resistance is unclear. In the diabetic heart, diminished activities of GLUT-4 results in reduced glucose utilization and impaired insulin signaling. This subsequently increases energy demand from FFA oxidation, raising myocardial oxygen demand and reducing cardiac efficiency, accompanied by dyslipidemia and lipotoxicity (Finck et al., 2003; How et al., 2006). Other potential drivers of cardiac insulin resistance include mitochondrial dysfunction, inflammation, cytokine upregulation, endoplasmic reticulum stress and stress kinase signaling (Gray & Kim, 2011). As metabolic derangements and insulin resistance precede the development of cardiac dysfunction and remodeling, these likely predispose the diabetic heart to damage. 2.1.3. Metabolic disturbances in diabetes: implications for the heart Disturbances in energy metabolism of the heart have been implicated as important contributors to diabetic cardiac complications (Belke et al., 2000; Buchanan et al., 2005; Wang et al., 2006; Bugger & Abel, 2010; Lopaschuk et al., 2010). For the purpose of this review, we have provided a short summary on the changes in metabolism evident in diabetes [for an extensive review of altered substrate metabolism in diabetes, please refer to (Boden, 2003; Raz et al., 2005)]. At the cellular level, mitochondrial dysfunction in particular plays a significant contribution to the development and progression of both cardiac and vascular complications of diabetes. This has recently been extensively reviewed elsewhere (Bugger & Abel, 2010; Dhalla et al., 2012; Dhalla et al., 2013; Galloway & Yoon, 2013). Alterations in mitochondrial morphology, (un)coupling, fission–fusion dynamics, Ca2+ load, substrate utilization and ATP generation are clearly both evident in, and exerting detrimental effects on the function of, the diabetic myocardium. Mitochondria also contribute as a pathophysiological trigger of diabetic cardiomyopathy as a key source of ROS in the heart, as detailed in Section 2.2 below. Hypertriglyceridemia is a common feature of T2DM, characterized by decreased clearance of triglyceride-rich lipoprotein, due to a reduction in the levels of lipoprotein lipase or alterations in circulating lipoproteins (Rodrigues et al., 1998). Various human and animal studies have been conducted to correlate the level of triglycerides with the degree of myocardial damage. The Framingham Study identified plasma triglyceride levels as a strong risk factor for development of diabetesinduced cardiac disease (Kannel & McGee, 1979). Elevated triglyceride levels correlate with the severity of atherosclerosis and coronary heart disease in diabetic patients (Tkac et al., 1997; Wild & Byrne, 2004). In animal models of diabetes, non-specific plasma lipid-lowering approaches (hydralazine and L-carnitine) result in concomitant prevention of both hyperlipidemia and cardiac dysfunction (Rodrigues et al., 1986; Rodrigues et al., 1990). FFA levels are also elevated in T2DM, which may shed light on the mechanistic relationship between increased fat, insulin resistance, impaired glucose tolerance and central obesity. FFAs are the primary energy substrate used by the heart, and are supplied to cardiac cells via

Table 1 Summary of animal models of diabetes. ↓, Reduced; Elevated; ↔, No change; ND, not determined. Models of type 1 diabetes

Streptozotocin

Akita

OVE26

BioBreeding

Type of model

Chemically induced

Genetically derived

Genetically derived

Genetically derived

rat/mouse

mouse

mouse

rat

Cardiac systolic function Cardiac diastolic function LV mass Cardiomyocyte size Myocardial fibrosis Systemic oxidative stress Cardiac oxidative stress Cardiac Ca2+ handling Cardiac mitochondrial function References

↓/↔ ↓ ↔ ↑ ↑ ↑ ↑ ↓ ↓ (Tomita et al., 1996; Ishikawa et al., 1999; Ferko et al., 2006; Yu et al., 2007; Huynh et al., 2010; Ritchie et al., 2012)

↔ ↓ ↓/↔ ND ND ↔ ↔ ↓ ↓ (Lu et al., 2007; Bugger et al., 2008; Basu et al., 2009; LaRocca et al., 2012)

↓ ↓ ↑ ↑ ↑ ↑ ↑ ↓ ↓ (Shen et al., 2004; Song et al., 2007; Li et al., 2011; Xie et al., 2011)

↓ ↓ ↑ ND ↑ ↑ ND ↓ ND (Rodrigues & McNeill, 1990; Katayama et al., 1994; Giles et al., 1998; Prasad, 2000; Ren & Bode, 2000; Loganathan et al., 2012; Tang et al., 2013)

Models of type 2 diabetes

ob/ob

db/db1

Zucker diabetic

Goto-Kakizaki

High fat-fed

High fructose

High sucrose

High milk fat fed

Type of model

Genetically derived

Genetically derived

Genetically derived

Genetically derived

Diet induced

Diet induced

Diet induced

Diet induced

Species

mouse

mouse

rat

rat

rat/mouse

rat/mouse

rat/mouse

mouse

Cardiac systolic function Cardiac diastolic function LV mass Cardiomyocyte size Myocardial fibrosis Systemic oxidative stress Cardiac oxidative stress Cardiac Ca2+ handling Cardiac mitochondrial function References

↓

↓

↓

↓

↓

↓

↓

↓

↓

↓

↓

↓

↓

↔

↓

↓

↑ ↑

↑ ↑

↑ ↔

↑/↔ ↑

↑/↔ ↑

↔ ND

ND ND

↑ ND

↑

↑

↔

ND

↑

↑

ND

ND

↑

↑

↑

ND

↑

↑

↑

ND

↑

↑

↑

ND

↑

↑

↑

ND

↓

↓

↓

↓

↓

↓

↓

ND

↓

↓

↓

ND

↓

ND

↔

ND

(Barouch et al., 2003; Boudina et al., 2005; Dong et al., 2006; Ren et al., 2010; Zibadi et al., 2011)

(Semeniuk et al., 2002; Buchanan et al., 2005; Boudina et al., 2007; Huynh et al., 2012)

(Chatham & Seymour, 2002; Baynes & Murray, 2009; Daniels et al., 2012; Howarth et al., 2012)

(Santos et al., 2003; El-Omar et al., 2004; Rose et al., 2007; Vahtola et al., 2008; Giroux et al., 2010; D'Souza et al., 2011)

(Aubin et al., 2008; Sutherland et al., 2008; Cole et al., 2011; Hua et al., 2012; Rindler et al., 2012)

(Axelsen et al., 2010; Mellor et al., 2011; Mellor et al., 2012)

(Dutta et al., 2001; Ryu & Cha, 2003; Carvajal et al., 2005; Vasanji et al., 2006; Diniz et al., 2008)

(Russo et al., 2012)

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Species

This cardiac phenotype in the db/db diabetic mouse can be affected by the background strain of the mouse (e.g. C57BL/6) and the stage of diabetes (e.g. 14–20 weeks of age).

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both endogenous sources (lipolysis of triglycerides in the heart) or exogenous sources (from the blood, as FFA bound to albumin, or via lipoproteins) (Rodrigues et al., 1998). Under insulin-deficient states, there is an increase in adipose tissue lipolysis and thus increased FFA released into the plasma. FFA levels are elevated in pre-diabetic patients with impaired glucose tolerance (Golay et al., 1988), and both acute and chronic increases in FFA levels are sufficient to induce insulin resistance (Boden, 2003). Altered energy metabolism in the diabetic heart is evident, with changes in substrate availability (both glucose and FFAs, see Taegtmeyer et al., 2002; Yoshimura et al., 2008; Lopaschuk et al., 2010). The accumulation of triglycerides and non-esterified fatty acids (NEFA) are thought to be involved in potentiating diabetes and its associated complications. High circulating and cellular FFAs can directly elevate peripheral insulin resistance, stimulate apoptosis and trigger a harmful build-up of toxic intermediates which result in lipotoxicity. These deleterious effects can contribute to impaired cardiac function and adverse remodeling in the diabetic myocardium (Nakayama et al., 2001; Shivu et al., 2010; Sun et al., 2012). The diabetic heart is also characterized by inefficient utilization of glucose for energy production. FFAs can inhibit glucose oxidation by activating proliferation activated receptor-α (PPAR-α) which increased the expression of pyruvate dehydrogenase kinase-4, mediating enhanced mitochondrial fatty acid uptake and reduced glucose oxidation (Hopkins et al., 2003). Cardiac glucose utilization is also reduced through depleted GLUT-4 expression and activity, which further contributes to aberrant myocardial morphology (Kaczmarczyk et al., 2003). The inability to switch to glucose oxidation renders the heart susceptible to damage and dysfunction under settings of reduced oxygen delivery, such as in myocardial ischemia (Stanley et al., 1997). Reduced glucose uptake and metabolism post-ischemia may compromise the capacity of the diabetic heart to recover, and several in vivo studies demonstrate greater LV dysfunction and severe structural remodeling in diabetic animals following short-term occlusion of the coronary artery (Feuvray et al., 1979; Paulson, 1997; Greer et al., 2006). 2.1.4. Neurohormonal activation Neurohormonal activation evident in the diabetic heart includes upregulation of the RAAS, ET-1 and sympathetic nervous system. Circulating Ang II, ET-1, the natriuretic peptides ANP and BNP, as well as catecholamines (epinephrine and norepinephrine) are also elevated (Takahashi et al., 1990; Makino & Kamata, 1998; Schneider et al., 2002; Wang et al., 2006; van der Horst et al., 2010; Forbes & Cooper, 2013). The neurohormonal plasma profile of diabetic patients with HF is however generally similar to non-diabetic HF patients, with the exception of BNP, where plasma levels are further elevated in diabetic HF patients, perhaps as a result of diastolic dysfunction (van der Horst et al., 2010) for which BNP has been considered as a prognostic marker. The role of the RAAS and ET-1 are discussed here. 2.1.4.1. Renin–angiotensin–aldosterone system. Increased activation of the RAAS is an important contributing mechanism to the functional structural abnormalities observed in the diabetic heart (Wang et al., 2006). The RAAS plays a pivotal role in the preservation of hemodynamic stability, through its ability to regulate blood pressure and maintain water and electrolyte balance (Forbes & Cooper, 2013). Renin triggers this hormonal cascade; both its synthesis by the renal juxtaglomerular apparatus and subsequent release from the kidney, in response to decreases in blood volume and renal perfusion, is tightly-regulated (Perazella & Setaro, 2003; Hsueh & Wyne, 2011). Serial cleavage of angiotensinogen (by renin, to form angiotensin I, Ang I), and then Ang I (by the zinc metallopeptidase, ACE) produces the biologically-active peptide, Ang II, to elicit both local tissue and systemic actions. Major sites of ACE synthesis include lungs, endothelial cells, heart, kidneys and brain. Interestingly a chymase that represents an alternative enzymatic source of Ang II independent from ACE is detected in mast cells and many cardiovascular and renal tissues, that can also cleave Ang I

to generate Ang II (Hideaki & Hidenori, 2013; Kennedy et al., 2013). Given its localization in mast cells, this chymase may contribute to the now-emerging causal role of inflammation in many cardiovascular disorders (as discussed in Section 3.3). Inhibition of this chymase is yet to be realized as a clinical application however. The RAAS serves as a safeguard against hemodynamic collapse (for example, in response to loss of blood, water or sodium); overactivation of the RAAS in pathological settings however results in excessive vasoconstriction, with eventual hypertrophy and fibrosis (Perazella & Setaro, 2003; Wong et al., 2004). The plethora of biological Ang II effects include potent vasoconstrictor actions, interaction with the sympathetic nervous system to increase vascular tone, aldosterone secretion and sodium retention, which subsequently increase arterial blood pressure (Perazella & Setaro, 2003; Hsueh & Wyne, 2011). Ang II also inhibits the release of renin to form a negative feedback loop for the RAAS cascade. Pathophysiological actions of Ang II include vascular smooth muscle cell proliferation and hypertrophy (Daemen et al., 1991; Itoh et al., 1993), in addition to cardiomyocyte hypertrophy (Ritchie et al., 1998a,b; Rosenkranz et al., 2000; Rosenkranz et al., 2002; Rosenkranz et al., 2003; Laskowski et al., 2006; Lin et al., 2012), as well as both LV hypertrophy (LVH), cardiac fibrosis and cardiomyocyte apoptosis in vivo (Sadoshima & Izumo, 1993; Sadoshima et al., 1993; Kawano et al., 2000; Singh et al., 2008b). The majority of the most well-known Ang II actions are thought to be predominantly mediated through the stimulation of angiotensin II type 1 (AT1) receptors (Timmermans et al., 1993; Hsueh & Wyne, 2011), although emerging roles for other angiotensin receptor subtypes are reported (Widdop et al., 2008). Moreover, intracellular generation of Ang II is sufficient to induce cardiomyocyte hypertrophy, as shown with a cardiomyocyte-selective adenovirus (AdV) administration of Ang II. A plasmid vector comprising oligonucleotides coding for Ang II amino acids inserted in the 3′untranslated region of ANP, downstream of an α-myosin heavy chain promoter, triggers cardiomyocyte hypertrophy in vitro and LVH in vivo, accompanied by TGF-β upregulation, without changes in plasma Ang II levels (Baker et al., 2004). Pathological LVH is an important risk factor for the development of HF, contributing to declining LV systolic function and abnormal diastolic filling in addition to disturbances in heart rhythm (Wachtell et al., 2000); LVH regression is thus associated with a more favorable prognosis (Verdecchia et al., 1998). Upregulation of the RAAS is evident in diabetes (both systemic and at the tissue level), and is considered to play an important role in the development of the cardiovascular complications of the disease (McFarlane et al., 2003; Cohen-Solal et al., 2008; van der Horst et al., 2010; Putnam et al., 2012). High glucose directly stimulates local Ang II production in vascular smooth muscle cells, cardiomyocytes and cardiac fibroblasts, via intracellular upregulation of components of the RAAS, particularly ACE, with additional contribution from both renin and chymase (Natarajan et al., 1999; Lavrentyev et al., 2007; Singh et al., 2007; Singh et al., 2008a,b). Regulation of intracellular Ang II generation appears to be tissue and cell-type specific, and can be independent of the regulation of the circulating RAAS. For example, cardiomyocyte Ang II generation in the diabetic rat heart is markedly upregulated, considerably more so than circulating levels of the peptide (Singh et al., 2008b). 2.1.4.2. Endothelin-1 system. In addition to its ability to increase activation of the RAAS, hyperglycemia also stimulates increased ET-1 levels in both clinical and experimental settings (Takahashi et al., 1990; Makino & Kamata, 1998; Schneider et al., 2002). Due to its potent vasoconstriction and pro-inflammatory actions, its ability to stimulate ROS generation, and its pro-hypertensive properties, upregulation of ET-1 concentration may have direct implications on cardiovascular function in diabetes (Kiowski et al., 1995; Schneider et al., 2002; Xu et al., 2004; Davidson et al., 2010). Elevated ET-1 levels in diabetic patients have been associated with the development of cardiac fibrosis through the accumulation of fibroblasts, mediated by the ET-1-induced endothelial-to-

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383

NADPH oxidase

Nox2 Rac

p67

p22 p40

p47

H2O2

•OH NADP+ + NADPH + O2 •O2-

H2O + O2

•O2•O2-

•O2•O2

BH4

•O2-

NO Mitochondrial respiratory chain

•O2-

•O2-

•O2-

eNOS BH2

ONOO-

Fig. 2. Sources of ROS in the heart. A summary of the major sources of ROS generation in the heart. Superoxide, the parent ROS, can be generated by the enzyme NADPH oxidase, as a byproduct of ATP production in the mitochondrial respiratory chain or by the uncoupling of eNOS. Superoxide can be converted to hydrogen peroxide in the presence of SOD, which can be further converted to hydroxyl radicals via the Fenton reaction. In the presence of NO, superoxide is converted to peroxynitrite. •O2−, superoxide; H2O2, hydrogen peroxide; •OH, hydroxyl radical; ONOO−, peroxynitrite eNOS, eNOS, endothelial nitric oxide synthase; SOD, superoxide dismutase, BH4, tetrahydrobiopterin (see text for references).

mesenchymal transition process (Widyantoro et al., 2010). Targeted ET1 gene silencing abolishes this transition, and attenuates the development of cardiac fibrosis. Furthermore, chronic ET-1 receptor blockade significantly improves LV developed pressure (LVDP) and the peak rate of rise of LV pressure, LV + dP/dt, in STZ-diabetic rats with depressed function, in addition to normalizing the exaggerated contractile response of mesenteric arteries to ET-1 (Verma et al., 2011). 2.2. Oxidative stress in the diabetic heart Despite the importance of diabetic cardiomyopathy as a clinical entity, the pathological cellular and molecular mechanisms driving the adverse changes in diabetic myocardial structure and function have not been fully resolved. The development and progression of diabetic complications is frequently attributed to increased oxidative stress. Molecular oxygen in its ground state is relatively inert and therefore is unable to accept electrons from other biological molecules (Selemidis et al., 2008). However, the enzyme-driven addition of electrons to the oxygen molecules greatly increases their reactivity, giving rise to a family of ROS. The oxidizing capability of ROS is used by aerobic cells to modulate the function and activity of cell signaling molecules; this process, however, must be tightly regulated by antioxidants to prevent oxidative damage (Bonnefont-Rousselot et al., 2000; Maritim et al., 2003; Selemidis et al., 2008). Oxidative stress thus results from an imbalance between the generation of ROS and the ability of the biological system to detoxify reactive intermediates (Wold et al., 2005). ROS include free radicals (which have at least one unpaired electron) such as the parent ROS superoxide (•O2−) and hydroxyl radical (•OH), and non-radicals which are able to generate free radicals (e.g., hydrogen peroxide H2O2) (Seddon et al., 2007). One cellular source of •O2− generation is as a byproduct of mitochondrial respiration. Under physiological conditions, endogenous superoxide dismutase (SOD) enzymes degrade •O2− to form the more stable species, H2O2, and O2. H2O2 is further broken down to water by the antioxidants glutathione peroxidase (GPx) and catalase. In pathological states, H2O2 can also generate the highly reactive •OH. Peroxynitrite (ONOO−) is also produced in excess under pathological settings, as a result of the reaction between •O2− and NO• (Seddon et al., 2007). ROS may induce numerous pathophysiological effects on the cell, depending on their concentration and location. Excessive production of ROS is thought to play a significant role in the development of various pathologies, due to their ability to directly oxidize DNA, proteins and lipid membranes

(Wold et al., 2005; Murdoch et al., 2006). In addition to this ability to inflict direct molecular damage, ROS may also activate stress-sensitive pathways of cellular damage (Evans et al., 2003). Many studies have linked diabetes to increased generation of ROS (Fig. 1), and/or a reduction in antioxidant defenses (Bonnefont-Rousselot et al., 2000; Maritim et al., 2003; Johansen et al., 2005). The predominant sources of ROS in the heart are likely to be derived from nicotinamide adenine dinucleotide phosphate (NADPH) oxidases, mitochondrial sources and uncoupled NO synthases (NOS), as discussed below (illustrated in Fig. 2). Although other enzyme sources of ROS may be present in the heart, including lipoxygenase, cyclooxygenase and xanthine oxidase, these alternate ROS sources are considered to be more minor contributors to cardiac ROS (Sugamura & Keaney, 2011). 2.2.1. Sources of reactive oxygen species in the heart 2.2.1.1. Nicotinamide adenine dinucleotide phosphate oxidase. The membrane-bound enzyme complex NADPH oxidase is a major source of ROS in cardiovascular cells such as cardiomyocytes, vascular smooth muscle, endothelial cells and adventitial fibroblasts (Li et al., 2002; Selemidis et al., 2008). Activity of NADPH oxidase can be triggered by a range of stimuli, including Ang II, ET-1 and tumor necrosis factor-α (TNF-α) (De Keulenaer et al., 1998; Pagano et al., 1998; Moller, 2000; Li et al., 2003; Nakagami et al., 2003; Laskowski et al., 2006). NADPH oxidase is the only source of ROS whose explicit role is to specifically generate ROS (rather than as a byproduct of other actions). Under pathological states, NADPH oxidase produces •O2− to destroy invading microbes (Lambeth, 2004). Each NADPH oxidase complex is comprised of a membrane-bound flavocytochrome, encompassing p22phox and a Nox subunit (usually either Nox1, Nox2 or Nox4), in addition to up to four additional regulatory subunits: p47 phox , p67 phox , p40 phox and Rac1 (Drummond et al., 2011). The primary Nox subunit isoforms in cardiac cells are Nox2 and Nox4 (Laskowski et al., 2006; Ritchie et al., 2007; Xu et al., 2011), although Nox1 expression is inducible in certain pathologies (Ritchie et al., 2007). Upon activation, phosphorylation of p47phox ensues, and integrates with other regulatory subunits (e.g. p67phox, p40phox, Rac1), to form an active NADPH oxidase enzyme complex (Drummond et al., 2011), resulting in release of •O2−. The Nox5 NADPH oxidase subunit, expressed in humans, is absent from the rodent genome, and thus, relatively little is known about its cardiovascular physiology and

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pathophysiology (Drummond et al., 2011). Interestingly, Nox5 is not influenced by the known NADPH oxidase regulatory subunits, but is instead regulated by cytosolic Ca 2+ concentrations (Banfi et al., 2001). Nox5 is expressed in human coronary vasculature and cardiomyocytes (Guzik et al., 2008; Hahn et al., 2012; Ahmarani et al., 2013). Expression of Nox5 is upregulated in patients with evidence of coronary artery disease, as well as after MI (Guzik et al., 2008). The precise nature of the direct effect of this novel Nox isoform on the arterial wall however remains poorly understood. NADPH oxidase activity and expression are significantly upregulated in pressure-overload LV hypertrophy (Li et al., 2002; Byrne et al., 2003; Liu et al., 2010) and in advanced HF (Li et al., 2002; Qin et al., 2007; Zhang et al., 2009). Furthermore, upregulation of Nox1 and Nox2 subunits of NADPH oxidase is observed in T1DM, accompanied by myocardial hypertrophy and fibrosis (Ritchie et al., 2005; Ritchie & Delbridge, 2006; Huynh et al., 2013), with similar evidence in the insulin-resistant heart (Ritchie et al., 2007). The role of Nox5 in cardiac remodeling or indeed diabetic cardiomyopathy however remains unresolved. The NADPH oxidase inhibitor apocynin, which acts by impeding the assembly of p47phox and p67phox subunits, prevents activation of NAPDH oxidase activity and apoptosis in Ang IItreated cardiomyocytes (Qin et al., 2007), highlighting the role of this enzyme complex in mediating Ang II-induced cell injury. 2.2.1.2. Mitochondria. The mitochondrial respiratory chain is another major myocardial source of ROS in the heart. Mitochondria are the site of oxidative phosphorylation, where ATP is generated via the electron transport chain via the electron carriers nicotinamide adenine dinucleotide (NADH) and flavin adenine dinucletide (FADH2). •O2− is a byproduct of this energy-generating pathway (Brand et al., 2004). The small amount of ROS produced during mitochondrial respiration is usually broken down by endogenous antioxidants to form water in non-disease states. However, impaired antioxidant capacity in pathological settings, such as in the failing myocardium, may aggravate ROS accumulation and lead to increased oxidative stress (Shen et al., 2006). Blocking the transport of electrons at complex I of the mitochondrial respiratory chain enhances levels of •O2−; moreover, mitochondria from failing hearts produce more •O2 − (Ide et al., 1999). Upregulated mitochondrial ROS production can be blunted via inhibition of the electron transfer complex, uncouplers of oxidative phosphorylation or by manganese superoxide dismutase (MnSOD) (Nishikawa et al., 2000). As a consequence of normalizing mitochondrial •O2− levels with these agents proposed mechanisms of oxidative stress-induced damage are also attenuated, including high glucoseinduced AGE formation, activation of pro-inflammatory NFκB (nuclear factor kappa-light-chain-enhancer of activated B cells), and sorbitol accumulation. 2.2.1.3. Uncoupled endothelial nitric oxide synthase (eNOS). eNOSdependant •O2− generation represents another source of ROS in the cardiovascular system. Under physiological conditions, the eNOS homodimer enzyme (comprising a reductase and an oxygenase domain), is the primary driver of NO• production in the vasculature. It functions to transfer electrons from NADPH (via the flavin adenine dinucleotide (FAD) and flavin mononucleotide (FMN) cofactors) to heme in the oxygenase domain. The substrate L-arginine, in the presence of cofactor tetrahydrobiopterin (BH4) is subsequently oxidized to L-citrulline and NO• (Forstermann, 2006). The tight regulation of eNOS-mediated electron transfer is crucial in preventing the uncoupling of O2 reduction from NO• generation, as each of the redox donors present in NOS enzymes (FAD, FMN, heme and BH4) are able to transfer electrons to O2. When eNOS is in its uncoupled state however, electrons transferred from the reductase to the oxygenase domain are donated to molecular oxygen instead of L-arginine, producing •O2−. eNOS uncoupling as a potent source of ROS generation has been observed in various disease settings, including diabetes and hypertension (Landmesser

et al., 2003; Thum et al., 2007a; Faria et al., 2012). For example, the endothelial dysfunction manifest in STZ-diabetic rats is associated with a reduction in BH4 levels and increased •O2− production (Cai et al., 2005). Moreover, supplementation of BH4 in diabetic patients improves endothelium-dependant vasodilation, indicating that increasing bioavailability of this essential cofactor can overcome eNOS uncoupling to maintain endothelial function (Heitzer et al., 2000). 2.2.2. Reactive oxygen species as a driver of cardiac remodeling Increased ROS can result in LV hypertrophy via several mechanisms, including elevated release of vasoactive peptides such as Ang II and ET-1, activation of redox-sensitive protein kinases such as c-jun N-terminal protein kinase (JNK) and p38 mitogen-activated protein kinase (p38MAPK), and mechanical stretch (Gray et al., 1998; Ruwhof & van der Laarse, 2000; Zhang et al., 2003; Weber et al., 2005). Several antioxidant-based studies have demonstrated a link between the hypertrophic process and increased cardiomyocyte generation of ROS. TNF-α and Ang II-induced cardiomyocyte hypertrophy is blunted by antioxidant treatment (butylated hydroxyanisole, vitamin E), suggesting that cardiomyocyte hypertrophy is mediated by increased ROS (Nakamura et al., 1998). Furthermore, antioxidants such as probucol, tempol and N-acetylcysteine are effective in reducing cardiomyocyte hypertrophy, by preventing Ang II-induced de novo protein synthesis and ANP expression, through inhibition of myocardial •O2− production (Nakagami et al., 2003). Increased NADPH oxidase-derived ROS production occurs in parallel with progression of pressureoverload LVH in vivo (Bendall et al., 2002; Li et al., 2002). The selective NADPH oxidase inhibitor apocynin significantly attenuates LV •O2− generation and expression of p22phox concomitant with normalization of LV weight in hypertensive rats in vivo (Park et al., 2004). Similarly, Ang II-induced cardiac hypertrophy is blunted by ablation of Nox2, on hypertrophic markers including heart weight: body weight ratio (HW: BW), LV myocyte area and expression of ANP and β-myosin heavy chain (Bendall et al., 2002). Collectively, these studies suggest that increased ROS production, in particular NADPH oxidase-dependant ROS generation, plays an important role in the pathophysiology and progression of cardiomyocyte hypertrophy. Enhanced interstitial collagen deposition is another important feature of cardiac remodeling. Various studies have suggested that oxidative stress is also an important regulator of pro-fibrotic processes, in myocardium and other tissues (Poli & Parola, 1997; Bendall et al., 2002; Johar et al., 2004; Chen & Mehta, 2006; Johar et al., 2006; Zhao et al., 2008). In particular, NADPH oxidase-dependant ROS production also contributes to the development of LV interstitial fibrosis. In Nox 2−/− mice, increases in myocardial collagen content induced by Ang II or pressure-overload are completely blocked, with lower pro-collagen I and III expression and suppressed matrix metalloproteinase, MMP2, activation (Bendall et al., 2002; Johar et al., 2004) (Grieve et al., 2006). The NADPH oxidase inhibitor apocynin similarly reduces cardiac procollagen I expression and collagen deposition in hypertensive rats (Park et al., 2004). Several mechanisms are thought to be implicated in NADPH oxidase-dependant pro-fibrotic effects, including increased activation of MMPs, expression of pro-fibrotic genes and activation of pro-inflammatory NFκB (Seddon et al., 2007). Reduction of ROS generation and restoration of redox balance may thus be important in preventing or treating myocardial fibrosis in the failing heart. The contributing components of cardiac remodeling, namely cardiomyocyte hypertrophy and cardiac fibrosis, to HFPEF versus systolic heart failure may be somewhat different. Both cardiomyocyte hypertrophy and cardiac fibrosis are evident in HFPEF, but the latter can be more prominent in systolic heart failure. Recent commentaries (e.g. Alagiakrishnan et al., 2013; Paulus & Tschope, 2013) suggest the paradigm of HFPEF in essence develops from a cascade of events initiated by the occurrence of one or more comorbidities that lead to upregulation of inflammation and ROS, both at the systemic and coronary endothelial level. These then impact on adjacent cardiomyocytes to impair

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NO signaling responses and passive tension, and induce hypertrophy (which is often concentric in nature). Diabetes, obesity and hypertension represent 3 of at least 5 likely initiating comorbidities of HFPEF. In contrast to HFPEF, myocardial dysfunction in systolic heart failure may have a greater reliance on cardiomyocyte-generated ROS and subsequent extracellular matrix deposition (Alagiakrishnan et al., 2013; Paulus & Tschope, 2013). Understanding of the phenotype of, and contributing mechanisms to, HFPEF, and how it compares and contrasts with systolic heart failure, is however continuing to evolve. 2.2.3. Reactive oxygen species negatively regulate cardiac function Increased ROS formation also plays an integral role in LV dysfunction. Direct application of ROS such as hydroxyl radical for 2 min markedly impairs both developed and diastolic force in mouse papillary muscles within 5–10 min, indicative of systolic and diastolic dysfunction, respectively (Hiranandani et al., 2006). Even short-term ROS exposure of the more stable, less reactive species H2O2 is sufficient to impair cardiomyocyte cell shortening in vitro, with cell arrest during diastole by 20 min (Kuster et al., 2010). These direct effects of ROS on cardiac function in isolated myocardial preparations are evident in the intact heart in vivo, as evidenced by the favorable effects of pharmacological and transgenic antioxidant approaches in the experimental models of HF (Ambrosio et al., 1986; Judy et al., 1991; Langsjoen et al., 1997; Salvemini et al., 2002; Yamamoto et al., 2003; Molyneux et al., 2008; Kumar et al., 2009; Lancel et al., 2010; Samuel et al., 2010; Adluri et al., 2011) and the detrimental impact of antioxidant deficiency (Mortensen et al., 1984; Folkers et al., 1985; Li et al., 1995; Yamamoto et al., 2003; Molyneux et al., 2008). 2.2.4. Role of reactive oxygen species in diabetic cardiac complications Diabetes upregulates major ROS sources in the heart (Fig. 1), including NADPH oxidase and mitochondrial generation of ROS, directly contributing to diabetic cardiomyopathy (Nishikawa et al., 2000; Huynh et al., 2012; Huynh et al., 2013). Several experimental and clinical studies have highlighted hyperglycemia-induced alterations in redox state as a key stimulator of these cardiac impairments. Elevated ROS generation in response to high glucose directly elicits apoptosis (Ho et al., 2000; Cai et al., 2002; Ho et al., 2006). Elevated glucose levels have been linked to several other biological pathways involved in the oxidative stress-induced complications of diabetes. Increased glucose oxidation in the cytoplasm increases the levels of reducing equivalents such as NADH, a substrate for mitochondrial respiration and thus for mitochondrial ROS generation, contributing to elevated production of mitochondrial •O2− (Haidara et al., 2006; Jay et al., 2006). Other proposed mechanism of diabetes-induced oxidative stress is the metabolism of glucose at high intracellular concentrations through the polyol pathway (Chung et al., 2003), in which glucose is reduced by the enzyme aldose reductase to form sorbitol, which is further oxidized to form fructose. Aldose reductase requires NADPH as a co-factor, and thus increased glucose metabolism through the polyol pathway leads to a concomitant decrease in intracellular stores of NADPH (Bonnefont-Rousselot et al., 2000).

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As the diabetic heart possesses a lower content of antioxidants in comparison to other organs, it is particularly susceptible to oxidative damage (Aliciguzel et al., 2003). Several markers of myocardial fibrosis in a rodent model of T1DM, including increased protein content of collagens I and IV, as well as TGF-β1 gene and protein expression, are inhibited by the antioxidant steroid hormone, dehydroepiandrosterone in vivo (Aragno et al., 2008). Cardiac insulin resistance induced by cardiac-specific deletion of GLUT-4 also highlights the association between NADPH oxidase upregulation and the development of structural impairments, with increases in several markers of cardiac hypertrophy (cardiac index, β-myosin heavy chain expression) accompanied by increased Nox1 and Nox2 expression of (Ritchie et al., 2007). Further, LV dysfunction in diabetic patients correlates with serum levels of the antioxidant enzyme, GPx (suggestive of a state of oxidative stress) (Gonzalez-Vilchez et al., 2005). 2.2.5. Impact of diabetes on the endogenous antioxidant defense system The balance between the generation of ROS and their removal via antioxidant degradation is critical for the maintenance of cardiovascular health. Under settings of oxidative stress, ROS that are not eliminated from cellular compartments by endogenous antioxidant defenses can cause irreparable damage to cellular macromolecules including nucleic acids, lipids and proteins (Maiese et al., 2007). Aerobic organisms maintain a sophisticated antioxidant defense system to counteract the physiological generation of ROS, which work both enzymatically and non-enzymatically to eliminate free radical intermediates or repair oxidation of cellular macromolecules (Maritim et al., 2003). Endogenous enzymatic and non-enzymatic antioxidants include SOD, GPx, catalase, thioredoxin (Trx), vitamin E and coenzyme Q10 (Maritim et al., 2003; Cave et al., 2005) (Table 2). Both hyperglycemia and diabetes are thought to directly impair the endogenous antioxidant defense system (Bonnefont-Rousselot et al., 2000), as detailed below. 2.2.5.1. Superoxide dismutase. SOD enzymes are metalloproteins responsible for catalyzing the dismutation of •O2− radical to molecular oxygen and hydrogen peroxide, thereby reducing intracellular •O2− levels. There are three major isoforms of SOD, distinguished by their localization in different cellular compartments. Copper–zinc SOD (CuZnSOD) is located in the cytoplasm and in the intermembrane space of the mitochondria (Crapo et al., 1992), MnSOD is found in the mitochondrial matrix (Shen et al., 2006), whereas extracellular SOD (ecSOD) resides in the extracellular matrix of tissues (Salvemini et al., 2002). Homozygous mutant mice lacking MnSOD die within the first 10 days of life with gross cardiac hypertrophy, endocardial fibrosis, consistent with dilated cardiomyopathy (Li et al., 1995). Although MnSOD ablation does not appear to affect cardiac mitochondrial ultrastructure, decreased levels of succinate dehydrogenase and aconitase activity suggest mitochondrial function is severely depressed, emphasizing the importance of MnSOD in protecting against mitochondrial •O2− release as a byproduct of oxidative phosphorylation. Mice deficient in the CuZnSOD isoform show

Table 2 Summary of the major endogenous antioxidants in mammals. Antioxidant

Function

Superoxide dismutase (SOD) Catalase Glutathione peroxidase (GPx) Thioredoxin (Trx) Vitamin E Ubiquinol (Coenzyme Q10)

Enzyme; converts superoxide to O2 and H2O2 Enzyme; converts H2O2 to oxygen and H2O Enzyme; converts hydroperoxides to H2O and alcohols Enzyme; reduction of protein cysteine–thiol disulfide bonds Lipid-soluble ROS scavenger; protects membranes from oxidation Lipid-soluble electron acceptor and ROS scavenger; protects membranes from oxidation

See text for references.

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normal growth and development through to early adulthood, but exhibit an overall reduction in lifespan, with extensive oxidative damage in the cytoplasm, nucleus and mitochondria, and increased incidence of hepatocarcinogenesis observed later in life (Elchuri et al., 2005). Thus, as •O2− is regarded as the parent ROS (released under physiological states from NADPH oxidase, the mitochondrial respiratory chain and eNOS uncoupling), the antioxidant properties of SOD are critical for maintaining oxidative balance. Diabetes impairs circulating and tissue (including heart, renal, hepatic and brain) SOD levels and/or activity (Kaul et al., 1995; Sundaram et al., 2012; Murali et al., 2013; Prabakaran & Ashokkumar, 2013; Yang et al., 2013). Moreover, diabetic patients exhibit reduced SOD expression (Ghattas & Abo-Elmatty, 2012; G.G. Wang et al., 2012). 2.2.5.2. Glutathione peroxidase and catalase. Accumulation of H2O2 and its decomposition product •OH is harmful for all aerobic organisms, facilitating the need for rapid and efficient removal via various antioxidant systems. Like SOD, catalase and GPx are capable of scavenging ROS and breaking redox cycles involved in the generation of ROS (Maritim et al., 2003). Catalase functions as a catalyst of the decomposition of H2O2 to O2 and H2O. GPx similarly functions as an antioxidant enzyme capable of reducing H2O2 and lipid peroxides to water and lipid alcohols, using glutathione as a hydrogen donor (Arthur, 2000). GPx1 is the most abundantly expressed GPx isoform, and is involved in most of the detoxification of H2O2 in the cytoplasm (Arthur, 2000). GPx1 protein levels are reduced in diabetic rats in vivo (Sindhu et al., 2004); this GPx1 deficiency upregulates cardiovascular pro-inflammatory and pro-fibrotic mechanisms, accelerating diabetes-induced atherosclerosis (Lewis et al., 2007). Both catalase and GPx levels are impaired in diabetes, across systemic, renal, brain and hepatic systems (Sundaram et al., 2012; Murali et al., 2013; Prabakaran & Ashokkumar, 2013; Yang et al., 2013). Cardiac GPx levels are also reduced in diabetes (Kaul et al., 1995; Sindhu et al., 2004), but the evidence is less convincing for cardiac catalase content (Maritim et al., 2003). Evidence of reduced catalase expression is also observed in diabetic patients (Ghattas & Abo-Elmatty, 2012). Moreover, a cohort of catalase-deficient Hungarian patients are reported as more susceptible to developing diabetes compared to the general population, suggesting catalase may actually regulate glycemic control, at least to some extent (Goth & Eaton, 2000). 2.2.5.3. Thioredoxin. One of the methods employed by the antioxidant defense system to lessen oxidative stress is by reversing oxidative damage from cellular macromolecules. Trx can detoxify peroxides through peroxiredoxins (Yamawaki & Berk, 2005). The Trx system, comprising thioredoxin, thioredoxin reductase and NADPH, is essential for the prevention of protein oxidation and damage, which under physiological conditions functions to maintain proteins in its reduced state (Yamawaki & Berk, 2005; Zschauer et al., 2013). Trx reduces oxidized cysteine residues present on proteins, forming a disulfide bond, which is subsequently reduced by thioredoxin reductase and NADPH. Trx exists in two forms in the mammalian cell: Trx1 and Trx2, which reside in the cytoplasm and in the mitochondria, respectively (Damdimopoulos et al., 2002). Trx activity can be induced under conditions of stress, including viral infection, ischemic insult, ultraviolet light, as well as in disease settings including heart disease and diabetes (Hotta et al., 1998; Yamawaki & Berk, 2005). Deficiency of active cardiac Trx induces LVH and increases oxidative stress, both of which are exaggerated following pressure-overload (Yamamoto et al., 2003). Trx has thus been suggested to be a negative regulator of cardiac hypertrophy (Ago & Sadoshima, 2007). High glucose conditions directly impair cardiomyocyte Trx activity in vitro, exaggerating a subsequent ischemia–reperfusion (I–R) injury response, suggesting that endogenous Trx activity is cardioprotective, and that this protection may be impaired in the diabetic heart (Luan et al., 2009). In recent years, the role of thioredoxin interacting protein (TxNIP), the endogenous Trx inhibitor, in the cardiovascular complications of diabetes and other

cardiovascular disorders has attracted significant interest. This has been reviewed extensively elsewhere (World & Berk, 2010; Lee et al., 2013; Zschauer et al., 2013). Of particular note however, there is now evidence that TxNIP is pro-oxidant in myocardium, and that genetic variations associated with increased TxNIP expression are linked to the incidence of diabetes and hypertension (Ferreira et al., 2012; He & Ma, 2012), highlighting the role of tight regulation of Trx-TxNIP interactions in maintaining cardiovascular health. A similar role is also evident in the kidney (Advani et al., 2009). 2.2.5.4. Vitamin C and vitamin E. Vitamin C, or ascorbic acid, functions as a water-soluble antioxidant by acting as a reducing agent to reverse oxidation. Loss of an electron coverts vitamin C to the ascorbyl radical (Padayatty et al., 2003). This can react with a wide variety of harmful oxidants including •O2− and •OH to form the more stable dehydroascorbic acid. In most mammalian species (but importantly not humans), vitamin C is synthesized from the hepatic metabolism of glucose (Paolisso et al., 1994). Vitamin E is a lipid-soluble antioxidant, which functions as a lipid peroxyl radical scavenger in vivo and a potential regulator of various cell signaling pathways (Yusuf et al., 2000). Vitamin E is localized to the cell membrane, where it functions to protect the cell against lipid peroxidation (via inhibition of the propagation, but not the initiation, components of this process) (Ernster & Dallner, 1994; James et al., 2004). Although vitamin E has been linked to reduced risk of coronary artery disease (Rimm et al., 1993), and epidemiological evidence suggests that both vitamin C and vitamin E intake may be important for mortality (Sahyoun et al., 1996), their prophylactic effects generally and in the diabetic population are not consistently observed (as discussed in Section 5). Both vitamin C and vitamin E levels are impaired in diabetes, across systemic, heart, kidney, liver and brain, often even where their dietary intake is normal (Salonen et al., 1995; Cunningham, 1998; Knekt et al., 1999; Elangovan et al., 2000; Suksomboon et al., 2011; Sundaram et al., 2012; Murali et al., 2013; Prabakaran & Ashokkumar, 2013; Saddala et al., 2013). 2.2.5.5. Coenzyme Q10. Endogenous coenzyme Q10 is localized to the hydrophobic region of the phospholipid bilayers, where it functions primarily as an electron transfer intermediate in the mitochondrial respiratory chain (Rauscher et al., 2001) (Fig. 3). Coenzyme Q10 is a critical component of this process, receiving electrons from various oxidoreductases including complex I, complex II and flavoprotein–ubiquinone oxidoreductase, to reduce ubiquinone to ubiquinol by the addition of two electrons and two protons (Bentinger et al., 2007). In addition to its role as an electron transfer intermediate, coenzyme Q10 also acts as an antioxidant in its reduced form (Bentinger et al., 2007). Its antioxidant actions largely rely on its ability to inhibit lipid peroxidation, thereby preventing the reaction of •OH and •O2− with neighboring lipid and protein molecules. The chain-breaking antioxidant properties of coenzyme Q10 also allow it to interfere with both the initiation and propagation steps involved in lipid peroxidation (Ernster & Dallner, 1994; James et al., 2004; Bentinger et al., 2007). Coenzyme Q10 is thus more effective at inhibiting lipid peroxidation than vitamin E; moreover, it can also further reduce lipid peroxidation by recycling vitamin E directly from the α-tocopherolxyl radical, a process dependent on the availability of water-soluble antioxidants such as ascorbate (Ernster & Dallner, 1994; James et al., 2004). Coenzyme Q10 localization to the hydrophobic region of membrane phospholipid bilayers, and its direct access to ROS-generating mitochondrial respiratory chain thus favor both prevention of lipid peroxyl radical formation and their removal via scavenging. Considerable information regarding the critical role of endogenous coenzyme Q10 in normal physiology has emerged from both in vitro and in vivo settings of coenzyme Q10 deficiency. Bioenergetic status is impaired (evident on cellular ATP:ADP ratios) and increases in ROS production, lipid peroxidation and cell death are observed in vitro (Lopez et al., 2010; Quinzii et al., 2010). Marked exercise intolerance and seizures are evident in vivo, with significant muscular apoptosis and lactic

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Growth factors

I

II

III IV

387

ATP synthase

Cell membrane

e1

2

CoQ e-

e- e -

FAD NAD+ ATP

3 Mitochondria

Coenzyme Q10

5 •O2•O2-

•O2-

4

Nucleus

Fig. 3. A schematic overview of the known cellular functions of coenzyme Q10. 1. Coenzyme Q10 protects the cell membrane against lipid peroxidation (due to its lipophilicity). 2. Coenzyme Q10 regulates growth factor function and enhances activity of other antioxidants. 3. Coenzyme Q10 improves cellular bioenergetics by enhancing mitochondrial function and enhancing mitochondrial ATP production (illustrated in the inset, which represents in inner mitochondrial membrane). 4. Coenzyme Q10 protects cells from nuclear DNA damage and inhibits apoptosis. 5. Coenzyme Q10 protects the cell against oxidative stress by scavenging (indicated by dashed line) reactive oxygen species (ROS, see text for references).

acidosis (Di Giovanni et al., 2001). Given the suggestion that coenzyme Q10 regulates cellular bioenergetic status (Kumar et al., 2009; Lopez et al., 2010; Quinzii et al., 2010), together with the high energy requirements of cardiomyocytes, it is perhaps not surprising that coenzyme Q10 is highly concentrated in the heart (Mortensen et al., 1984). Deficiency of endogenous coenzyme Q10 may even serve as a prognostic indicator for mortality in patients with HF (Mortensen et al., 1984; Folkers et al., 1985; Molyneux et al., 2008). Diabetes has been specifically reported to reduce endogenous coenzyme Q10 levels, across rodent kidney, liver and heart, as well as in the human circulation (Kucharska et al., 2000; Wittenstein et al., 2002; Lim et al., 2006; Sourris et al., 2012). There are intriguingly a small number of reports in which diabetes has in contrast been shown to upregulate antioxidant defenses [see (Maritim et al., 2003) for review], presumably in an effort to overcome the diabetes-induced upregulation of ROS and the subsequent detrimental consequences. Regardless of the impact of diabetes on endogenous antioxidant levels however, exogenous supplementation of antioxidant nutrients and pharmacological agents that mimic the actions of endogenous antioxidant enzymes have been shown to confer protection against diabetes-induced oxidative damage, which translated to both improved structure and function of the heart in settings of diabetic cardiomyopathy (Nakamura et al., 1998; BonnefontRousselot et al., 2000; Maritim et al., 2003; Ye et al., 2004; Ritchie et al., 2007; Suksomboon et al., 2011; Styskal et al., 2012). The use of traditional antioxidant approaches for the treatment of heart disease in diabetic animals is explored in Section 5 of this review, and of coenzyme Q10 in Section 6.

2.3. Altered Ca2+ handling in the diabetic heart 2.3.1. Mechanisms underlying impaired intracellular Ca2+ handling and cardiac dysfunction in diabetes The disturbance of Ca2+ regulation in the diabetic heart was first established more than two decades ago, where depressed myofibrillar ATPase activity and sarcoplasmic reticulum (SR) function were identified as contributing factors to the development of diabetic cardiomyopathy (Dillmann, 1980; Penpargkul et al., 1981; Pierce & Dhalla, 1981). A multitude of studies in experimental animals have since linked the contractile defects observed in the diabetic myocardium with an altered ability of the heart to regulate Ca2+, largely from animal models of diabetes (Lagadic-Gossmann et al., 1996; Ren & Bode, 2000; Belke et al., 2004; Shao et al., 2007; Kranstuber et al., 2012). Defects in one or more mechanisms which regulate intracellular Ca2+ concentration, including the sarcolemmal L-type Ca2+ channel, the SR Ca2+ release channel, SR Ca2+-ATPase (SERCA2a), the SERCA2a regulator phospholamban, ryanodine Ryr2 receptors and the sarcolemmal Na+/Ca2+ exchanger (NCX), have been implicated in diabetic cardiomyopathy (Choi et al., 2002; Bidasee et al., 2004; Pereira et al., 2006; Shao et al., 2007; Lebeche et al., 2008; Kranstuber et al., 2012). These defects may be evident in protein levels, gene expression, and/or activity of each of these regulators of cardiac Ca2+ metabolism. The regulation of Ca2+ signaling is a critical determinant of cardiomyocyte contractile function and relaxation. SERCA2a is responsible for Ca2+ re-uptake to initiate cardiomyocyte relaxation, and as such is a key modulator of cardiomyocyte function (Zarainherzberg et al., 1994). Cardiomyocytes isolated

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from T1DM rats for example exhibit reduced rise and fall of intracellular free Ca2+ concentrations, in parallel with a reduced rate of contraction and relaxation (Choi et al., 2002). Similar observations have been obtained in whole hearts from diabetic rats, in which reduced inotropy and lusitropy are accompanied by elevated end-diastolic Ca2+ levels and impaired transport capacity of SERCA2a activity (Ligeti et al., 2006). Diabetes-induced diastolic dysfunction, a key characteristic of diabetic cardiomyopathy, in particular has been attributed to impairment of myocardial Ca2+ handling. Diabetes affects both the enzymatic transport and the passive buffering of Ca2+ in and out of the cell (Teshima et al., 2000). In cardiomyocytes isolated from T1DM rats (in which diastolic dysfunction and preserved systolic function are evident in vivo), action potential duration and are prolonged, with significant reductions in Ca2+ transient amplitude, SR Ca2+ load and SERCA2a protein levels (Lacombe et al., 2007). 2.3.2. Sarcoplasmic reticulum Ca2+ ATPase modulates cardiomyocyte relaxation The dysregulation of basal cardiomyocyte Ca2+ levels, and their oscillation during cardiac contraction–relaxation cycle, are largely attributable to changes in Ca2+ transport mechanisms. In particular, the SR Ca2+ pump SERCA2a, which plays a central role in the regulation of Ca2+, is defective in T1DM (Ganguly et al., 1983; Lopaschuk et al., 1983; Yu et al., 1994; Netticadan et al., 2001; Bidasee et al., 2004). Consequently, the re-uptake of Ca2+ by the SR is delayed. Many investigators have attributed the slowing of the cardiac relaxation in diabetes to reduced expression and/or function of this Ca2+-handling protein (Russ et al., 1991; Kim et al., 2001; Dutta et al., 2002; Davidoff et al., 2004; Sakata et al., 2006; Lacombe et al., 2007). These impairments are a direct result of hyperglycemia, as insulin supplementation normalizes SERCA2a activity and protein content (Lopaschuk et al., 1983; Netticadan et al., 2001; Bidasee et al., 2004). More recent reports have observed a similar relationship between defective SERCA2a activity and myocardial dysfunction in experimental models of T2DM. In db/db mice, increased cardiomyocyte Ca2+ leakage from the SR and prolonged SR Ca2+ re-uptake is accompanied by reduced LVSP, LV + dP/dt and LV-dP/dt in the intact heart ex vivo, compared to non-diabetic cardiomyocytes (Belke et al., 2004). Similar findings are observed in sucrose-fed insulin-resistant rats in vivo (Vasanji et al., 2006). Restoration of cytoplasmic Ca2+ concentrations following contraction is predominantly mediated through activation of SERCA2a and to a lesser extent, the sarcolemmal NCX. SERCA2a thus facilitates cardiac relaxation, allowing sufficient Ca2+ available for the following wave of contraction (Frank et al., 2003). Adequate SERCA2a activity is pivotal in preserving a balanced contraction–relaxation cycle (Bhupathy et al., 2007). SERCA2a and its regulator phospholamban form a complex whereby an increased SERCA2/phospholamban ratio increases Ca2+ reuptake (Kranias & Hajjar, 2012). Diabetes upregulates LV protein content and/or activity of phospholamban (Belke et al., 2004; Bidasee et al., 2004; Vasanji et al., 2006). Other investigators confirm that a decreased SERCA2a/phospholamban ratio is a significant contributing factor to the slowed cardiac relaxation in the diabetic heart (Vetter et al., 2002; Vasanji et al., 2004; Bhupathy et al., 2007). SERCA dysfunction likely contributes to both diastolic and systolic LV dysfunction, by prolonging cardiac relaxation and reducing the availability of SR Ca2+ for subsequent release and contraction (Kohlhaas & Maack, 2011). Although impaired SERCA2a function has implications for both diastolic and systolic performance, a reduced SR Ca2+ uptake in particular likely explains the prolonged rate of relaxation in the diabetic heart (Pierce et al., 1996). Approaches that elevate SERCA2a expression (increasing the number of SR Ca2+ pumps) (Hiranandani et al., 2006) and/or decrease phospholamban expression (Vasanji et al., 2006), enhance SR function, with increased capacity to sequester Ca2+ back to the SR during relaxation. Transgenic overexpression of SERCA2a in diabetic rats accelerated SR Ca2+ uptake, and partially restored diabetes-induced contractile dysfunction (Vetter et al., 2002); similar

benefits are observed with AdV-SERCA2a (Sakata et al., 2006). Moreover, SERCA2a overexpression overcomes hydroxyl radical-induced damage in murine papillary muscles ex vivo (Hiranandani et al., 2006). Despite these observations, some studies report no changes in SERCA2a expression in diabetic hearts, suggesting that dysfunctional cardiac relaxation in diabetic cardiomyopathy may be more attributable to the function of SERCA2a rather than its content per se (Lebeche et al., 2008). In several cardiac pathologies, SERCA2a is susceptible to posttranslational modifications that can alter its function (Adachi et al., 2004; Kuster et al., 2010; Tong et al., 2010). In the diabetic heart, SERCA2a function is particularly prone to post-translational modifications, for example as a result of increased levels of oxidative stress, ROS and/or AGE, as discussed below. 2.3.3. ROS impairs cardiomyocyte sarcoplasmic reticulum Ca2 + ATPase function Cysteine thiols on SERCA are particularly susceptible to posttranslational modifications as a result of oxidative stress (Adachi et al., 2004; Ying et al., 2008; Kuster et al., 2010; Tong et al., 2010). Considerable interest has focused on the SERCA 674Cys residue; irreversible thiol oxidation as evident in atherosclerosis, for example, significantly impairs vascular SERCA activity with slowing of SR Ca2+ re-uptake (Adachi et al., 2004). SERCA 674Cys-thiol oxidation is upregulated in diabetic hyperlipidemic aorta; correction of hyperglycemia with insulin prevents this SERCA modification (Ying et al., 2008). Acute exposure to ROS depletes cardiomyocyte SR Ca2+ content and inhibits SERCA2a activity (Kuster et al., 2010); the concomitant functional defects are associated with oxidative thiol modifications on SERCA2a. Mice overexpressing the heterotrimeric G protein subunit Gαq exhibit SERCA 674Cys-thiol oxidation, accompanied by marked impairments in cardiomyocyte SERCA2a activity, contractile function and relaxation (Lancel et al., 2010). Transgenic catalase expression attenuates all of these adverse changes, implicating ROSmediated post-translational SERCA2a modifications in this model of cardiomyopathy. Generation of reactive carbonyl species is upregulated in diabetes; these species can also induce post-translational modifications to SERCA2a in diabetic myocardium, via reactivity with its exposed arginine, lysine and histidine residues. As a consequence, both SERCA2a function and thus cardiomyocyte mechanical function are impaired (Shao et al., 2011), as confirmed by their sensitivity to the reactive carbonyl species scavenger pyridoxamine. Other reported oxidative modifications to SERCA2a include nitration at tyrosines 294/295 (Lancel et al., 2010). It is thus likely that adverse SERCA2a post-translational modifications (such as those mediated by ROS) may be a critical causal factor of SERCA2a dysfunction, and on a larger scale may be a primary contributor to myocardial dysfunction within diabetes. 2.4. Advanced glycation end product modification in the diabetic heart AGE formation results from non-enzymatic, covalent binding of amine residues on proteins or lipids and sugar moieties such as glucose; in the diabetic setting, chronic hyperglycemia upregulates AGE formation (Jay et al., 2006; Goh & Cooper, 2008; Jandeleit-Dahm & Cooper, 2008; Yamagishi et al., 2012). AGE modification of proteins can take the form of a single, isolated alteration on a peptide chain, or complexes consisting of multiple AGE modifications cross-linking several protein molecules (Aronson, 2003; Forbes & Cooper, 2013). Diabetes significantly increases the cardiac content of AGEs and of their receptor, RAGE; both likely contribute to the pathogenesis of diabetic cardiomyopathy (Candido et al., 2003; Bidasee et al., 2004; Ma et al., 2009), similar to their role in the vascular complications of the disease (Goh & Cooper, 2008; Jandeleit-Dahm & Cooper, 2008; Ramasamy et al., 2012; Yamagishi et al., 2012). Proteins with slower rates of turnover, such as the ECM proteins collagen and elastin, are particularly susceptible to AGE modification (Wang et al., 2006; Goh & Cooper, 2008). The first evidence that AGE contributed to diabetic cardiomyopathy was the

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the alleviation of diabetes-induced prolongation of cardiomyocyte cytosolic Ca2+ transients clearance and reduced SR Ca2+ load with the AGE cross-link breaker alagebrium chloride (Kranstuber et al., 2012). Therapeutic strategies which are aimed at preventing adverse SERCA2a posttranslational modifications, such as AGE cross-link breakers or antioxidants, may prevent diastolic and systolic failure in the diabetic heart.

observation that the AGE cross-link breaker alagebrium chloride (ALT-711) prevents diabetes-induced LV expression of BNP and pro-collagen III, as well as both deposition and solubility of LV collagen in vivo. LV CTGF levels were also blunted (Candido et al., 2003). Importantly, these morphological benefits conferred by alagebrium chloride translate to improvements in LV diastolic function, attenuating diabetes-induced prolongation of IVRT and deceleration time (derived from echocardiography) (Kranstuber et al., 2012). As demonstrated by Ma et al., the diabetes induced upregulation of cardiac AGE–RAGE levels (and their colocalization) is evident even in individual diabetic rat cardiomyocytes (Ma et al., 2009). Moreover, targeting the AGE–RAGE axis in vivo, with the AGE formation inhibitor benfotiamine, or small interfering RNA (siRNA) against RAGE, significantly attenuated the diabetes-induced cardiomyocyte impairments in contractile function or relaxation (determined on cell shortening and relengthening, respectively) (Ma et al., 2009). The impact of diabetes in vivo on cardiomyocyte function is replicated by exposure of control cardiomyocytes to methylglyoxal-modified bovine serum albumin treatment in vitro; this RAGE-mediated response is exaggerated in diabetic cardiomyocytes. LV systolic and diastolic function are similarly preserved by siRNA-RAGE in diabetic myocardium ex vivo. Neither inhibition of AGE nor RAGE impacted on circulating glucose, triglyceride or cholesterol levels (Ma et al., 2009). AGE formation also represents another mechanism of glucose-induced oxidative stress, via RAGE activation, with subsequent activation of NADPH oxidase and redox-sensitive transcription factors (including NFκB) and other pro-inflammatory mediators (Haidara et al., 2006; Jay et al., 2006; Yamagishi et al., 2012), likely further contributing to cardiovascular diabetic complications. These data clearly implicate the AGE–RAGE axis in the pathogenesis of diabetic cardiomyopathy. SERCA2a also has a relatively slow turnover rate and is thus also susceptible to AGE modification (Wang et al., 2006; Goh & Cooper, 2008). Increased LV formation of AGE-SERCA2a adducts is thus a likely key mechanism by which AGE–RAGE impairs diabetes-induced LV diastolic dysfunction. MALDI-TOF mass spectra of diabetic rat myocardium reveals formation of several amino acid-AGE adducts on SERCA2a that are absent from sham and insulin-treated diabetic animals (Bidasee et al., 2004). These AGE-SERCA2a adducts impair SERCA function, as suggested by

2.5. O-linked beta-N-acetylglucosamine protein modification in the diabetic heart 2.5.1. Physiological regulation of the hexosamine biosynthesis pathway (HBP) The HBP is an alternative fate of glucose that diverts a small amount of fructose-6-phosphate away from glycolysis, leading to O-GlcNAcylation, a post-translational modification involving the addition and removal of the O-linked β-N-acetylglucosamine (O-GlcNAc) sugar moiety. Under normal physiological conditions, it is estimated that up to 5% of glucose available in the cytoplasm is shuttled through HBP, rather than glycolysis (as shown in Fig. 4) (Hart et al., 2007; Cieniewski-Bernard et al., 2009; Laczy et al., 2009; Mellor et al., 2010; Ngoh et al., 2010; Slawson et al., 2010; Teo et al., 2010; Zeidan & Hart, 2010). Fructose-6-phosphate is the point of divergence between these two pathways. The HBP commences with the conversion of fructose-6-phosphate to glucosamine-6-phosphate via the rate-limiting enzyme, GFAT (glutamine:fructose-6-phosphate amidotransferase). Further metabolism to incorporate the nucleotide UDP generates UDP-Nacetylglucosamine (UDP-GlcNAc) (Slawson et al., 2010; Teo et al., 2010; Zeidan & Hart, 2010). This moiety can then modify proteins, either by well-known pathways involving the endoplasmic reticulum (ER) and Golgi, or the more recently described pathway, cytosolic/nuclear Olinked glycosylation. During this process, a single monosaccharide, OGlcNAc, is O-link-attached via several enzymatic steps to the hydroxyl (–OH) side chain of serine or threonine residues on a broad range (~1000 identified so far) of nucleocytoplasmic proteins (Davidoff, 2006; Hart et al., 2007; Slawson et al., 2010; Teo et al., 2010; Zeidan & Hart, 2010). O-GlcNAcylation of a protein is a reversible, dynamic process, with relatively rapid addition (O-GlcNAcylation) and removal

glucose

glucose-6- P

2-5%

fructose-6- P

GFAT hexosamine biosynthesis pathway glucosamine-6 - P

glycogen synthesis

>95%

glycolysis

UDP-GlcNAc

Diabetes

UDP

GlcNAc O

+

Ser/Thr

HO

OGT

Ser/Thr

OGA

sustained ↑↑ protein-O-GlcNAc

O-GlcNAcylated protein

GlcNAc

unmodified protein

myocardial function Fig. 4. Diabetes upregulates HBP/O-GlcNAc pathways in the diabetic heart. Under normal physiology, the hexosamine biosynthesis pathway diverts a small amount of fructose-6phosphate away from glycolysis to generate the O-GlcNAc moiety, which is added and removed in a dynamic fashion to specific serine and threonine residues on a range of proteins to regulate their function and is cytoprotective. This process is upregulated in a sustained fashion in diabetes, which is detrimental and a likely contributor to cardiac and other complications of diabetes (see text for references).

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(deGlcNAcylation) of the O-GlcNAc sugar group, similar to the addition and removal of the phosphate group that is characteristic of phosphorylation/dephosphorylation. The enzymes O-GlcNAc transferase (OGT) and β-N-acetylglucosaminidase (or “O-GlcNAc-ase”, OGA) add and remove the O-GlcNAc moiety, respectively (Hart et al., 2007; Zeidan & Hart, 2010). Both OGT and OGA are highly conserved enzymes; both are present in the cytoplasm and nucleus (Hart et al., 2007; Zeidan & Hart, 2010). Most of our understanding of O-GlcNAc protein modification has been derived from adipose tissue, skeletal muscle, neuronal and other non-cardiac tissues. Until recently, it was thought to function solely as a cell sensor to nutrients and stress (Butkinaree et al., 2010; Chatham & Marchase, 2010b; Slawson et al., 2010; Wellen & Thompson, 2010). Proteins susceptible to this dynamic process include transcription factors, regulators of translation, cytoskeletal components and other nucleo-cytoplasmic proteins (Kohler, 2010). Marked cross-talk occurs between the enzymes responsible for O-GlcNAc cycling and phosphorylation/dephosphorylation. Protein O-GlcNAcylation often occurs at the same sites as phosphorylation, or in quite close proximity. Thus, modification of a protein by O-GlcNAc may affect its potential to undergo phosphorylation at the same or adjacent serine/threonine residues (Brownlee, 2005; Slawson et al., 2010; Zeidan & Hart, 2010). Excitingly, the crystal structure of human OGT is emerging (Lazarus et al., 2011). With ongoing development of O-GlcNAc antibodies and hexosaminidase inhibitors (Gross et al., 2005; Hart et al., 2007; Dorfmueller et al., 2011), we anticipate an exponential interrogation of the role of HBP/O-GlcNAc signaling in both cardiac physiology and pathophysiological settings. 2.5.2. Acute upregulation of hexosamine biosynthesis pathway/O-linked beta-N-acetylglucosamine signaling is cardioprotective In normal physiology, transient activation (usually minutes-tohours) of HBP/O-GlcNAc pathways is an adaptive mechanism to enhance cell survival. Interventions that acutely reduce cellular OGT and/ or total cellular O-GlcNAc levels in vitro decreases stress-tolerance, whereas the converse scenario enhances cell survival (Hart et al., 2007; Chatham & Marchase, 2010b). The teleological purpose of acute upregulation of HBP/O-GlcNAc signaling is thus likely cytoprotective (Zachara et al., 2004; Ngoh et al., 2010). There is convincing evidence for this in the heart, particularly with respect to both pathological hypertrophy and MI. Enhanced O-GlcNAc signaling is evident within one week after pressure-overload hypertrophy in mice, with similar observations in isolated cardiomyocytes exposed to hypertrophic stimuli for 48 h in culture (Facundo et al., 2012). Both AdV-OGA or pharmacological GFAT inhibition 2–24 h prior limited cardiomyocyte hypertrophy in vitro (Facundo et al., 2012). In contrast, inducible cardiomyocyte OGT deficiency shortly prior to pressure-overload hypertrophy exaggerates the HF response in mice (Watson et al., 2010), although it is without impact on LV function on its own. Upregulated O-GlcNAc signaling is also observed in experimental settings of myocardial I–R injury, in isolated cardiomyocytes, isolated perfused hearts or in MI in vivo (Yang et al., 2006; Fulop et al., 2007a; Liu et al., 2007a,b; Zou et al., 2007; Champattanachai et al., 2008; Jones et al., 2008; Ngoh et al., 2008; Zou et al., 2009; Ngoh et al., 2011). Targeting HBP/O-GlcNAc signaling, using both pharmacological and gene-based therapies consistently yields cardioprotective effects with upregulated HBP/O-GlcNAc, with the converse applying when HBP/O-GlcNAc signaling is blunted, in each of the experimental scenarios (Ngoh et al., 2011). Interestingly, the beneficial consequences of blunting cardiac HBP/O-GlcNAc signaling are associated with ROS suppression (Ngoh et al., 2011), enhanced mitochondrial function and cell viability (Chatham & Marchase, 2010a; Darley-Usmar et al., 2012). Thus, acute upregulation of HBP/O-GlcNAc signaling is cardioprotective, both in vitro (2–48 h) and in vivo (1 h–1 week). 2.5.3. Sustained activation of hexosamine biosynthesis pathway/O-linked beta-N-acetylglucosamine pathways is detrimental In contrast to the above contexts, strong recent evidence now indicates that sustained (i.e. over several weeks in vivo, in contrast to

acute) O-GlcNAcylation is detrimental, particularly in the context of diabetes or cancer, with sustained HBP/O-GlcNAc signaling-induced impaired mitochondrial function a likely contributing mechanism (Chatham & Marchase, 2010a; Darley-Usmar et al., 2012). Further, in adipose tissue, skeletal muscle and kidney, sustained activation of O-GlcNAcylation is a clear contributing mechanism to the development of insulin resistance (McClain & Crook, 1996; Slawson et al., 2010; Teo et al., 2010), and as an important mediator of the complications of diabetes (McClain & Crook, 1996; Laczy et al., 2009; Slawson et al., 2010; Teo et al., 2010). In both skeletal muscle and adipose tissue, insulin resistance is prevented by blocking GFAT (the rate-limiting enzyme in the pathway), whereas GFAT overexpression induces insulin resistance (Marshall et al., 1991; Cooksey & McClain, 2002; McClain et al., 2002). GFAT gene expression and activity is upregulated in diabetic patients (Slawson et al., 2010). Subjects carrying a single nucleotide polymorphism in the gene encoding OGA (which impairs their ability to remove the O-GlcNAc moiety) carry a 3-fold increased risk of developing T2DM (Lehman et al., 2005), highlighting the relevance of hexosamine biosynthesis and O-GlcNAc protein modification in diabetes. Importantly, O-GlcNAc protein modifications are distinct from other types of glucose-modifications also implicated in the complications of diabetes, such as that associated with advanced glycation (e.g. AGEs). In contrast to AGE formation, O-GlcNAc protein modification is a dynamic, reversible intracellular process, there are no further changes to the O-GlcNAc group itself, and O-GlcNAc does not form long, chainlike structures or form crosslink formations with extracellular matrix proteins such as collagen (Candido et al., 2003; Lebeche et al., 2008; Butkinaree et al., 2010; Zeidan & Hart, 2010). 2.5.4. Upregulation of hexosamine biosynthesis pathway/ O-linked beta-N-acetylglucosamine pathways in the diabetic heart Elevated glucose associated with diabetes is considered to have an adverse effect on the heart. HBP has emerged as a novel contributor to diabetic cardiac complications downstream of impaired glycemic control (Cieniewski-Bernard et al., 2009; Laczy et al., 2009; Mellor et al., 2010; Ngoh et al., 2010; Teo et al., 2010). The HBP/O-GlcNAc machinery is detected in human myocardium (Nerlich et al., 1998), and its activity is upregulated in experimental settings of both T1DM and T2DM (Clark et al., 2003; Hu et al., 2005; Fulop et al., 2007b). This is mimicked in high glucose-treated cardiomyocytes in vitro (Fiordaliso et al., 2001; Rajamani & Essop, 2010). In the context of diabetic heart disease, until relatively recently very little was known about the long-term consequences of sustained activation of HBP/O-GlcNAc pathways in the heart, but these have now emerged as important mediators of impairments in both myocardial excitation–contraction coupling, LV dysfunction and cardiomyocyte viability, as well as insulin responsiveness (Davidoff, 2006; Lebeche et al., 2008; Rajamani & Essop, 2010). Increased flux though HBP/O-GlcNAc pathways occurs in parallel to AGE formation; both represent mechanisms identified in the pathogenesis of the vascular complications of diabetes downstream of hyperglycemia (Brownlee, 2005; Davidoff, 2006; Laczy et al., 2009). Adenoviral OGA expression rescues both the downregulation of SERCA2a expression and the prolongation of cardiomyocyte Ca2+ transient decay induced by prolonged high glucose levels in vitro, whereas OGT mimics the effects of high glucose (Clark et al., 2003). In STZ-induced T1DM mice, LV AdV-OGA expression ameliorates diabetes-induced upregulation of total O-GlcNAC content as well as cardiomyocyte function (Hu et al., 2005). Similarly, GFAT inhibition abrogates (while exogenous O-GlcNAc exaggerates) high glucose-induced cardiomyocyte apoptosis (Rajamani & Essop, 2010). Phospholamban, the negative regulator of SERCA2a, is O-GlcNAc modified in the STZ T1DM rat heart in vivo, likely increasing its brake on SERCA2a function, and contributing to diastolic dysfunction in diabetes (Yokoe et al., 2010). Furthermore, both total cardiac O-GlcNAc content (Clark et al., 2003; Hu et al., 2005; Fulop et al., 2007b), and cardiac O-GlcNAc modification of actin (Ramirez-Correa et al., 2008) are increased in obesity. The potential for O-GlcNAc protein

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modification of SERCA, phospholamban, cardiac contractile proteins or other targets relevant for LV function have however not been studied in T2DM. Given that hyperglycemia and obesity individually are sufficient to O-GlcNAcylate other cardiac contractile proteins (as discussed above), it is however highly likely that these are similarly affected in T2DM, exacerbating LV function. Evidence from cultured cells suggests that the interaction between HBP/O-GlcNAc and ROS signaling in the context of diabetes is a bidirectional interaction (and quite distinct to that seen in other cardiac pathologies, as outlined above) (Lima et al., 2012). Prolonged high glucose conditions triggers upregulation of both HBP/O-GlcNAc signaling and ROS generation, which are blunted by anti-oxidant interventions (Du et al., 2000) and OGT knockdown (Goldberg et al., 2011), respectively. OGT knockdown also blunts profibrotic protein content in vitro (Goldberg et al., 2011). To our knowledge, no evidence regarding this ROS-HBP/O-GlcNAc interaction has yet been sought specifically in the diabetic heart. We and others thus propose a causal role for O-GlcNAc protein modification in diabetic cardiomyopathy, and that targeting the consequences of sustained HBP/O-GlcNAc signaling may represent a new strategy for limiting diabetes-induced LV dysfunction (Fig. 4). 2.6. Dysregulation of microRNAs There is increasing evidence that a relatively new class of tiny noncoding genes, called microRNAs (miRNAs), which have profound roles in a number of diseases, may contribute to the pathogenesis of diabetic cardiomyopathy. Recent studies in cell culture, animal models of diabetic cardiomyopathy and diabetic HF patients have identified miRNAs expressed in this disease and are delineating their role in diabetic cardiomyopathy. miRNAs are a group of short (~22 nucleotides long) single-stranded non-coding RNA molecules that are widely expressed in both plants and animals and conserved across mammalian species. miRNAs have a critical role in a range of biological processes (e.g. development, apoptosis, oncogenesis) where they regulate gene activity by causing mRNA degradation or inhibition of protein synthesis (Bernardo et al., 2012a; van Rooij & Olson, 2012). Thus, it is not surprising that miRNAs have been implicated in a wide range of different diseases, including cancer (Farazi et al., 2011), cardiovascular disease (Van Rooij et al., 2008; Catalucci et al., 2009; Bernardo et al., 2012b), and metabolic disorders such as diabetes (Kolfschoten et al., 2009; Guay et al., 2011). While it has been reported that miRNAs play a major role in heart development and function (Zhao et al., 2007; Chen et al., 2008) and pathological cardiac hypertrophy (Van Rooij et al., 2006; Sayed et al., 2007; Bernardo et al., 2012b), relatively little attention has been given to the role and expression of miRNAs specifically in diabetic cardiomyopathy [for other reviews see (Kantharidis et al., 2011; Asrih & Steffens, 2013; Shantikumar et al., 2012)]. A number of studies have performed miRNA expression profiling in STZ T1DM mice to identify differentially expressed miRNAs and their target genes in diabetesinduced cardiomyopathy (Feng et al., 2010; Diao et al., 2011; Shen et al., 2011). A study by Feng et al. (Feng et al., 2010) demonstrates significant alteration of a large number of miRNAs in cardiac tissue from diabetic compared with non-diabetic mice (14 upregulated including miR-9-5p, -146b, -187, -203, -299-5p, -324-5p, -341, -362, -371, -374, -431, -487a, -500, -518d; and 28 downregulated miRs including miR-1, -16, -20a, -23b, -24, -26a, 30a-5p, -30d, -93, -122a, -133a, -133b, -146a, -197, -207, -297, -320, -326, -335, -345, -346, 369-5p, -370, -422b, -432-5p, -467, -483, -497). Of these, a muscle-specific miRNA, miR-133a is significantly downregulated, as has been previously shown in non-diabetic cardiac hypertrophy (Care et al., 2007). Exposure of neonatal cardiomyocytes to high glucose also decreases miR-133a expression, with increased cell size and expression of ANP and BNP. However, transfection of high glucose-exposed neonatal cardiomyocytes with miR-133a mimics (synthetic oligonucleotides

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that increase the expression of miR-133a) prevents glucose-induced cardiomyocyte hypertrophy (Feng et al., 2010). The proposed mechanism by which miR-133a may regulate diabetes-induced cardiomyocyte hypertrophy is through serum and glucocorticoid-regulated kinase 1 (SGK1) and insulin like growth factor-1 receptor (IGF-1R), which are upregulated in diabetic hearts and in cardiomyocytes exposed to high glucose, but downregulated with miR-133a mimic transfection (Feng et al., 2010). Genetic inhibition of SGK1 in a mouse model of pressure overload-induced HF mitigates development of HF and fibrosis that is associated with pressure overload (Das et al., 2012), which lends further support to the proposed mechanism by which miR-133a and SGK1 may regulate diabetes-induced cardiomyopathy. Diao et al. (Diao et al., 2011) performed miRNA array profiling and gene ontology analysis of target gene functions in hearts of STZinduced diabetic and control mice. This study identified 10 miRNAs (miR-195, -199a-3p, -700, -705, -142-3p, -24, -21, -208, -221 and 4993p) as upregulated, and 6 miRNAs as downregulated (-29a, -1, -373, -143, -20a, -220b) in diabetic hearts compared to control mice. Given that some of these miRNAs are implicated in cardiac dysfunction and HF in mice in separate studies [e.g. miR-1 (Care et al., 2007), -208 (Callis et al., 2009), -195 (Van Rooij et al., 2006)] this group of miRNAs identified by Diao et al. (Diao et al., 2011) may also be involved in the pathogenesis of diabetic cardiomyopathy. The same authors (Shen et al., 2011) later demonstrated a role of miR-373 in mediating glucose induced cardiomyocyte hypertrophy through myocyte enhancer factor2C (MEF2C) (Kolodziejczyk et al., 1999). Over-expression of miR-373 in neonatal cardiomyocytes exposed to high glucose decreases cell surface area compared to high glucose and reduces MEF2C protein levels (Shen et al., 2011). It has been documented that diabetic cardiomyopathy is associated with a reduction in Pim-1 (pro-viral integration site for Moloney murine leukemia virus-1), which has a key role in cardiomyocyte function and survival (Muraski et al., 2008; Katare et al., 2010). Pim-1 protein levels decline in STZ diabetic mouse hearts and adult rat cardiomyocytes cultured under high glucose conditions (Katare et al., 2011). Pim-1 is a validated target of miR-1 (Nasser et al., 2008), a miRNA involved in pathological cardiac hypertrophy (Care et al., 2007; Elia et al., 2009). miRNA-1 expression is upregulated in STZ diabetic mice (Katare et al., 2011); inhibition of miRNA-1 in adult rat cardiomyocytes restores Pim-1 expression and promotes cardiomyocyte survival under high glucose conditions (Katare et al., 2011), providing a link between Pim-1 and miR-1 in diabetic cardiomyopathy. In T2DM, patients with ischemic HF exhibit significant cardiac modulation of a group of miRNAs (miR-34b, -34c, -199b, -210, -650, -223) relative to their non-diabetic counterparts, as recently shown using miRNA microarray profiling (Greco et al., 2012). Of these, miR-34b and -c are specifically upregulated in the remote ischemic zone of myocardium in diabetic HF, and in the border zone of both diabetic and non-diabetic HF. The miR-34 family (-a,-b,-c) is known to be upregulated in HF, both subsequent to MI (Lin et al., 2010) and in patients with end-stage HF (Thum et al., 2007b), and more recently following pressure overload (Bernardo et al., 2012b). Furthermore, inhibition of the miR-34 family in mice with pre-existing pathological LVH and LV dysfunction attenuates LVH, improves LV function, and decreases both fibrosis and the expression of cardiac stress genes (Bernardo et al., 2012b). The miR-34 family is also associated with the p53 tumor suppressor network (Vogelstein et al., 2000; Concepcion et al., 2012). As hyperglycemia promotes p53-dependent apoptosis (Fiordaliso et al., 2001), this suggests a possible link between p53/miR-34 and the hyperglycemia-induced death pathway (Greco et al., 2012). miR-210 is also activated in diabetic HF, although it remains unclear whether upregulation of miR-210 is cardioprotective. Both miR-210 and ROS-activated hypoxia-inducible factor (HIF) signaling are involved in the hypoxic response (Devlin et al., 2011); HIF is also induced in the myocardium in diabetic HF (Giordano, 2005; Greco et al., 2012).

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Epigenetic regulation plays a crucial role in the consequences of diabetes, including diabetic cardiomyopathy (Brasacchio et al., 2009; Nikoshkov et al., 2011; Asrih & Steffens, 2013). DNA methylation is the principle form of epigenetic regulation and is induced in diabetic hearts (Nikoshkov et al., 2011). Evidence is now emerging that miRNAs also target the epigenetic machinery. miR-133a is a known regulator of cardiac hypertrophy and diabetes (Care et al., 2007; Feng et al., 2010; Chavali et al., 2012). In diabetic insulin 2-mutant Akita mice, which develop cardiomyopathy by 3 months of age, cardiac miR-133a is downregulated, and the levels of de novo and maintenance DNA methyltransferases are either elevated (Dnmt-1, -3b) or downregulated (Dnmt-3a), suggesting cross-talk between these DNA methyltransferases. High glucose upregulates Dnmt-1 and downregulates Dnmt-3a and -3b expression in a cardiomyocyte-like cell line (HL-1, derived from an adult murine atrial cardiomyocyte tumor), all of which are attenuated by overexpression of miR-133a, suggesting that miR-133a inhibits DNA methylation in diabetic cardiomyocytes (Chavali et al., 2012). Hyperglycemia initiates the expression and activation of the transcriptional coactivator p300, a trigger of the expression of pivotal regulators of cardiomyocyte hypertrophy (Duan et al., 2013). This p300 expression and activation is also subject to regulation by miRs, of note miR-150, which decreases in pathological cardiac hypertrophy (Van Rooij et al., 2006; Sayed et al., 2007; Tatsuguchi et al., 2007). Similar evidence of reduced miR-150 expression is evident in both diabetic rat heart in vivo, and in high glucose-treated cardiomyocytes in vitro (Duan et al., 2013). This downregulation of miR-150 is accompanied by increased p300 gene expression and protein levels in both diabetic myocardium and high glucose cardiomyocytes, with evidence of binding of miR-150 to p300 with luciferase reporter assays. Further, miR150 mimics prevent both the high glucose-induced upregulation of p300 (at the gene and protein level), as well as hypertrophic responses (on increased cardiomyocyte size and cardiac fetal gene expression). Together, these observations demonstrate that miR-150 functions as a suppressor of high-glucose induced p300 expression (Duan et al., 2013). Collectively, these studies demonstrate that diabetic cardiomyopathy is associated with a deregulated miRNA expression pattern that, in part, overlaps with a HF miRNA signature pattern. Further studies are required to determine whether diabetic cardiomyopathy is associated with a specific miRNA expression pattern different to that of HF, and to elucidate the precise mechanisms of miRNAs in diabetic cardiomyopathy, which may allow for the development of appropriate new therapeutic treatments. 3. Signaling pathways implicated in diabetic cardiomyopathy A number of signaling proteins and pathways have been implicated in contributing to the development of diabetic cardiomyopathy including protein kinase C (PKC), NFκB pathway, PPARα, PI3K, and MAPKs. Triggers activating these proteins and pathways include high glucose, increased activation of the RAS, elevated FFAs, oxidative stress and pro-inflammatory mediators (see Fig. 5). 3.1. Activation of protein kinase C PKC signaling is activated in the heart in response to hyperglycemia, as well as growth factors that are elevated in a setting of diabetes, including Ang II (Ishii et al., 1996; Rajagopalan et al., 1996; Naruse & King, 2000; Idris et al., 2001; Way et al., 2001; Inoguchi et al., 2003; Davidoff et al., 2004). A build-up of metabolites involved in the glycolysis pathway drives formation of diacylglycerol (DAG), which is a critical activating cofactor for PKC isoforms. Hyperglycemia-mediated activation of PKC is associated with a host of downstream protein and gene expression changes which can contribute to characteristic features of the diabetic heart including cardiac fibrosis (TGF-β, CTGF and plasminogen activator inhibitor-1) (Koya et al., 1997; Way et al., 2002),

hypertrophy (via activation of MAPKs) (Braz et al., 2002), inflammation (TNF-α, NFκB) (Li et al., 1999; Devaraj et al., 2005; Chand et al., 2012) and oxidative stress (via activation of NADPH oxidase) (Inoguchi et al., 2003; Geraldes & King, 2010). There are more than 10 PKC isoforms and at least 4 (α, β, δ, ε) are associated with mediating cardiac hypertrophy and/or pathology (Bernardo et al., 2010). Both PKCα and PKCβ isoforms are upregulated in the diabetic heart (Inoguchi et al., 1992; Guo et al., 2003). Transgenic overexpression of PKCβ2 specifically in cardiac myocytes results in significant cardiac hypertrophy, cardiomyocyte necrosis, fibrosis and reduces cardiac performance, coupled with upregulation of TGF-β1, β-myosin heavy chain and collagen gene expression (Wakasaki et al., 1997). PKCα is also associated with impaired contractility and propensity towards HF, due to an adverse effect on Ca2+ handling in cardiomyocytes (Wakasaki et al., 1997; Hahn et al., 2003; Braz et al., 2004). A number of studies have assessed the protective properties of PKC isoform-specific inhibitors in settings of myocardial I–R injury and MI (Hahn et al., 2002; Boyle et al., 2005; Young et al., 2005; Liu et al., 2009); less is known in settings of diabetic cardiomyopathy. Connelly et al. assessed the potential of the PKCβ inhibitor ruboxistaurin in diabetic rats with diastolic HF. Six weeks of PKCβ inhibitor treatment preserves LV diastolic function and SERCA2a expression; cardiomyocyte hypertrophy and LV collagen deposition were also attenuated compared with vehicle-treated diabetic rats (Connelly et al., 2009). Ruboxistaurin also protects against deficits in cardiac microvascular barrier function in diabetic rats (Wei et al., 2010). This is consistent with ruboxistaurin's ability to protect against diabetesinduced microvascular disorders such as diabetic retinopathy and nephropathy; currently under investigation in large patient trials (Dhalla & Muller, 2010; Geraldes & King, 2010). 3.2. Peroxisome proliferator-activated receptor signaling in the diabetic heart PPARs (α, β/δ and γ) belong to the nuclear receptor superfamily of transcription factors. Of the three PPAR isoforms, PPARα has been the most studied in the heart. Metabolic derangements are a key feature of the diabetic heart. Unlike the normal heart, the diabetic heart derives its energy almost exclusively from fatty acid metabolism (see Section 2.1). PPARα has relatively high expression in cardiac myocytes. PPARα signaling is activated by elevated FFA (see Fig. 5), which in turn regulates the expression of genes involved in fatty acid uptake and mitochondrial fatty acid oxidation in the heart (Desvergne & Wahli, 1999; Watanabe et al., 2000; Campbell et al., 2002; Kelly, 2003; Duncan, 2011). Transgenic mice with cardiacspecific overexpression of PPARα exhibit a cardiac phenotype reminiscent of diabetic cardiomyopathy, which includes LVH, systolic dysfunction, increased expression of ANP and BNP, and decreased expression of SERCA2a (Finck et al., 2002). Furthermore, the phenotype is associated with increased expression of genes involved in cardiac fatty acid uptake and oxidation, and suppression of genes involved in glucose transport and utilization. Conversely, PPARα deletion has an adverse effect on the heart. Global PPARα−/− mice display reduced cardiac fatty acid oxidation, associated with a pathological cardiac phenotype including progressive cardiac fibrosis (Watanabe et al., 2000). In comparison to PPARα, less is known about the function of other PPAR isoforms. Like PPARα, PPARβ/δ is expressed at high levels in the heart, and regulates metabolic genes in heart muscle cells (Gilde et al., 2003). Interestingly, the phenotype of cardiac-specific PPARβ/δ transgenic mice is quite distinct to that reported in cardiac-specific PPARα transgenic mice. Lipid accumulation and genes related to fatty acid oxidation are elevated in hearts of PPARα, but not PPARβ/δ, transgenic mice. PPARβ/δ overexpression enhances myocardial glucose utilization, activates cardiac glucose transport pathways and increases glycolytic gene expression (Burkart et al., 2007). Furthermore, PPARβ/δ transgenic mice have normal baseline cardiac function, and exhibit a reduced I–R injury response compared to non-transgenic or PPARα transgenic

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Fig. 5. Signaling cascades involved in the development of diabetic cardiomyopathy. Triggers of diabetes-induced cardiac damage include hyperglycemia, increased RAAS activation and altered Ca2+ handling regardless of diabetes etiology. Cardiac insulin resistance (characteristic of both type 1 and type 2 diabetes) also contributes. These triggers result in energy depletion, increased fibrosis, apoptosis and hypertrophy, and impaired LV contractile function and relaxation. AGEs, advanced glycation end-products; ASK1, apoptotic signal regulating kinase-1; FAO, fatty acid oxidation; GLUT-4, glucose transporter-4; GPCR, G protein coupled receptor; HBP, hexosamine biosynthesis pathway; IGF-1, insulin-like growth factor-1; JNK, c-Jun N-terminal kinase; NADPH, nicotinamide adenine dinucleotide phosphate; NCX, sodium–calcium exchanger; •O2− , superoxide; O-GlcNAc, O-linked beta-N-acetylglucosamine; p38, p38 MAPK; PI3K, phosphoinositide-3 kinase; PKCβ, protein kinase C-β; RTK, receptor tyrosine kinase; RyR, ryanodine receptor SERCA, sarcoplasmic reticulum Ca2+ ATPase; T1DM, type 1 diabetes mellitus; T2DM, type 2 diabetes mellitus. PI3K signaling attenuates signaling highlighted with a red asterisk (*). See text for references.

mice. Collectively this suggests that PPARα and PPARβ/δ have different metabolic regulatory processes within the heart (Burkart et al., 2007). A more recent study demonstrated that administration of a PPARβ/δ agonist for 3 weeks attenuates lipid-induced myocardial inflammation in mice fed a high fat diet. In contrast global PPARβ/δ display an enhanced pro-inflammatory profile in the heart (Alvarez-Guardia et al., 2011). PPARγ is predominantly expressed in white and brown adipose tissue, and has relatively low expression in the heart (Desvergne & Wahli, 1999). PPARγ agonists including thiazolidinediones (activators of PPARs, with highest specificity for PPARγ) are approved for the treatment of T2DM. While this class of drugs improves insulin sensitivity and glycemic control, and shows benefits in animal studies, the impact on cardiovascular risk in clinical trials remains unclear (Zhu et al., 2000; Yue et al., 2001; McGuire & Inzucchi, 2008). Of note however, cardiac-specific PPARγ transgenic mice display depressed cardiac function by 4 months of age, associated with increased expression of fatty acid oxidation genes (Son et al., 2007). 3.3. Pro-inflammatory mediators in the diabetic heart Inflammation is now considered to play an important role in the development and progression of a number of cardiovascular disorders. The influx of infiltrating inflammatory cells, likely secondary to upregulation of ROS, has emerged as a significant contributor to hypertension,

atherosclerosis, myocardial ischemia and chronic HF (Anker & von Haehling, 2004; Willerson & Ridker, 2004; Harrison & Gongora, 2009; Drummond et al., 2011; Bienvenu et al., 2012; Chan et al., 2012; Dinh et al., 2012; Swirski & Nahrendorf, 2013; Tabas & Glass, 2013). Moreover, systemic inflammation is an independent predictor of impairments in LV diastolic function (Chrysohoou et al., 2009). In diabetes, systemic inflammation is both evident and considered a contributing mechanism to systemic disease progression (Thorand et al., 2003; Dinh et al., 2009; Akash et al., 2013; Bryan et al., 2013). Upregulation of the pro-inflammatory cytokine TNF-α in clinical and experimental HF suggest the heart is a target of infiltrating inflammatory cells (Anker & von Haehling, 2004; Willerson & Ridker, 2004; Edgley et al., 2012; Oka et al., 2012; Rickard et al., 2012). Their infiltration into injured myocardium contributes significantly to myocardial necrosis and dysfunction after MI (Moens et al., 2005; Vinten-Johansen et al., 2005; Gao et al., 2011; Swirski & Nahrendorf, 2013; Tabas & Glass, 2013), but their contribution to cardiomyopathies of other etiologies has received less attention. Immunological changes in the diabetic myocardium, such as the upregulation of pro-inflammatory cytokines, chemokines, and the activation of various leukocyte populations, suggest that pro-inflammatory processes may also contribute to the pathogenesis of diabetic cardiomyopathy (Haffner, 2006). Indeed in diabetic patients, low-grade chronic systemic inflammation, as depicted by elevated plasma levels of cytokines (TNF-α and

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interleukin IL-6), is associated with diastolic dysfunction (Dinh et al., 2009). LV expression of TNF-α, interleukin IL-1β and cyclooxygenase COX2 are upregulated in diabetic rodents(Westermann et al., 2006; Westermann et al., 2007; Thandavarayan et al., 2011; Yar et al., 2011). Further, ROS upregulation is likely an important driver of diabetes-induced LV inflammation, as diabetes-induced LV upregulation of TNF-α and IL-1β is blunted by antioxidant interventions (Huynh et al., 2013). NFκB is a family of transcription factors that controls the expression of hundred of genes including pro-inflammatory genes, pro-fibrotic genes and hypertrophy-related genes (Dinh et al., 2009; Lorenzo et al., 2011; Yu et al., 2011). It has now been implicated as a key mediator of the inflammatory process in the diabetic heart (Mariappan et al., 2010; Lorenzo et al., 2011; Thandavarayan et al., 2011; Yar et al., 2011). Inflammatory molecules (monocyte chemoattractant protein-1, vascular cell adhesion molecule-1), hyperglycemia, ROS, hyperlipidemia, Ang II, and cytokines (e.g. interleukins, TNFα) can activate NFκB via their respective receptors, resulting in NFκB nuclear translocation (Dinh et al., 2009; Lorenzo et al., 2011; Yu et al., 2011). Increased cytokine (TNF-α, IL-6, IL-1β) and TGF-β protein levels in the T1DM heart is accompanied by significant systolic dysfunction; these are all attenuated by pharmacological inhibition of p38 MAPK (Westermann et al., 2006). Similarly, upregulation of IL-1β and TGF-β in the STZ diabetic heart is detected concomitantly with diastolic stiffness and increased fibrosis, all of which is attenuated by an AT1 antagonist (Westermann et al., 2007). Inflammatory mediators are also known to negatively regulate normal insulin signaling via the phosphorylation of insulin receptor substrate IRS1 at serine sites (Dandona et al., 2004; Shoelson et al., 2006). More recently, the role of cardiac NFκB in a model of T2DM was assessed, using the putative NFκB inhibitor (pyrrolidine dithiocarbamate, PDTC). Adult male 32-week-old obese db/db mice display depressed systolic function, elevated cardiac NFκB activity, increased circulating levels of TNFα and IL-6, and increased oxidative stress (LV ROS, superoxide and peroxynitrite) (Mariappan et al., 2010). PDTC treatment for 20 weeks from 12 weeks of age preserves cardiac function, and attenuates the elevation of other parameters. Given the structure of PDTC however, its protective properties are most likely due to its combined NFκB-inhibiting and ROS-scavenging actions (Mariappan et al., 2010). 3.4. The role of cardiac mitogen-activated protein kinase signaling MAPKs are a large family of serine/threonine specific-protein kinases that are categorized into four major subfamilies including extracellular signal-regulated kinases (ERK1/2), p38 MAPK (α, β, γ, δ isoforms), JNKs (JNK1, 2, 3) and big MAPK (BMK or ERK5) (Rose et al., 2010). The role of MAPKs in the regulation of cardiac growth and remodeling in settings of stress has been extensively described previously [see (Bernardo et al., 2010; Rose et al., 2010; Marber et al., 2011)]. Here, we focus on the potential role of MAPKs in the diabetic heart. 3.4.1. p38 mitogen-activated protein kinase There are four isoforms of p38 MAPK (α, β, γ, δ) which share structural homology, but differ in their sensitivity to pharmacological inhibition (Eyers et al., 1999; Marber et al., 2011). p38α MAPK is ubiquitously expressed, while p38γ is thought to be preferentially expressed in cardiac muscle (Lemke et al., 2001). Expression of p38β MAPK and p38δ MAPK is relatively limited in cardiac tissue (Dingar et al., 2010). A summary of the pathophysiological roles of each p38 MAPK isoform in the heart has been previously described (Marber et al., 2011). The p38 MAPK signaling transduction pathway is stimulated under high glucose conditions, as well as by stressors such as oxidants and pro-inflammatory cytokines, all of which are elevated in diabetes (Macfarlane et al., 1997; Igarashi et al., 1999; Wilmer et al., 2001). p38 MAPK is elevated in the hearts of diabetic animal models (Westermann et al., 2006; Thandavarayan et al., 2009; Li et al., 2012; Rajesh et al.,

2012). Westermann et al. demonstrated that treatment of STZ diabetic mice with a p38 MAPK inhibitor (SB 203580) for 8 weeks attenuates LV systolic dysfunction and prevents increased pro-inflammatory cytokine levels in the heart (Westermann et al., 2006). Similar protection is observed with cardiac-specific transgenic downregulation of p38α MAPK in diabetic mice. Diabetic dominant-negative p38α MAPK diabetic mice display preserved LV systolic function, reduced cardiomyocyte diameter, lower fibrosis, lower apoptosis and lower ANP expression compared to diabetic non-transgenic mice (Thandavarayan et al., 2009). Improvements in these parameters is accompanied by a reduction in markers of oxidative stress, including downregulated expression of NADPH oxidase subunits (e.g. Nox2 and p22phox) and decreased lipid peroxidation levels. Together, these observations suggest that p38 MAPK activity is necessary for the induction of adverse cardiac remodeling and dysfunction associated with diabetes. 3.4.2. Extracellular signal-regulated kinase 1/2 ERK1/2 activation can occur via G protein-coupled receptors, receptor tyrosine kinases and other cytokine receptors. The role of ERK1/2 in the heart is complex, linked with both adaptive and maladaptive heart growth [see (Bernardo et al., 2010)]. The functional role of ERK1/2 signaling in the diabetic heart remains unclear. While one study observed that the phosphorylation of ERK is elevated in diabetic rat and mouse hearts 1 week after STZ induction of diabetes (Strniskova et al., 2003), another failed to detect this in STZ diabetic mouse hearts assessed at 1, 3, 7, 28 and 56 days after the induction of diabetes (Gurusamy et al., 2004). More recently it was demonstrated that the phosphorylation of ERK is elevated in diabetic mouse hearts 5 months after STZ, and this is prevented in mice overexpressing the antioxidant metallothionein (Tan et al., 2011). Further, in HL-1 cardiomyocytes treated with H2O2, ERK-mediated inhibition of Nrf2 (NF-E2-related factor 2, a gene that regulates antioxidant enzymes) elicits oxidative stress and decreases glucose utilization. Collectively, these data suggest ERK1/2 may play an important role in the diabetic heart. 3.4.3. c-Jun N-terminal kinases JNKs are encoded by 3 genes; Jnk1 and Jnk2 are expressed ubiquitously, and Jnk3 expression is largely limited to the heart, brain and testis (Davis, 2000). JNK can be activated by inflammatory cytokines (eg. TNFα and IL-1) and insults such as increased oxidative stress (Davis, 2000). The phosphorylation of JNK is elevated in H9c2 cardiomyocyte-like cells exposed to high glucose (Kuo et al., 2013), and in T1DM mouse (Li et al., 2012; Rajesh et al., 2012). Further, pretreatment of cardiomyocytes with the JNK inhibitor SP600125 prior to exposure to high glucose significantly reduces the extent of apoptosis (Liang et al., 2010). However, whether JNK plays a causative role in the development of diabetic cardiomyopathy in vivo is unresolved. Of interest, overexpression of dn-JNK1 confers protection against pancreatic βislet cell destruction and subsequent hyperglycemia (Kaneto et al., 2002). Further, AdV-dn-JNK1 transfection in db/db obese diabetic mice liver reduces blood glucose levels and improves insulin resistance (Nakatani et al., 2004). 3.5. The role of cardiac phosphoinositide 3-kinase(p110α) signaling PI3Ks are a family of lipid kinases which activate multiple signaling cascades (Franke, 2008). PI3K(p110α) is a class IA PI3K which is activated by receptor tyrosine kinases including the insulin receptor and IGF-1R (Bernardo et al., 2010). PI3K(p110α) plays a pivotal role in the regulation of adaptive (physiological) cardiac growth, as opposed to maladaptive (pathological) cardiac growth which inevitably progresses onto HF (McMullen et al., 2003). Utilizing genetic mouse models it has been demonstrated that PI3K(p110α) is critical for physiological postnatal heart growth and adaptive exercise-induced heart growth and protection (Shioi et al., 2000; McMullen et al., 2003; Luo et al., 2005; Owen et al., 2009; Weeks et al., 2012). The IGF-1R is considered

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a key mediator upstream of PI3K(p110α), inducing physiological hypertrophy (McMullen et al., 2004). In contrast to physiological hypertrophy, the development of pathological hypertrophy is mediated by G-protein coupled receptor signaling, following activation by hormones such as Ang II and ET-1 (Luo et al., 2005). Bernardo et al. have extensively reviewed the molecular distinction between physiological and pathological cardiac hypertrophy (Bernardo et al., 2010). Studies using dominant negative PI3K mice (dnPI3K, reduced cardiac PI3K(p110α) activity) have shown that PI3K(p110α) is critical for protecting the heart in a number of cardiac stress settings including pressure overload, dilated cardiomyopathy, atrial fibrillation, and MI (McMullen et al., 2003, 2007; Pretorius et al., 2009; Lin et al., 2010; Weeks et al., 2012). More recently we examined the role of PI3K(p110α) in the STZ T1DM mouse heart in vivo (Ritchie et al., 2012). The development of diabetic cardiomyopathy (LV diastolic dysfunction, fibrosis and apoptosis) is accelerated in diabetic dnPI3K mice compared to non-transgenic diabetic mice. Interestingly, superoxide generation in the dnPI3K heart is elevated under both basal and diabetic settings. In contrast, transgenic mice with increased cardiac PI3K(p110α) activity due to transgenic overexpression of IGF1R or expression of a constitutively active (ca) PI3K mutant are protected against developing diabetic cardiomyopathy (Huynh et al., 2010; Ritchie et al., 2012). Further, expression of the caPI3K transgene prevents the diabetes-induced increase in LV superoxide generation (Ritchie et al., 2012). Collectively, these data demonstrate that reduced IGF-1R-PI3K(p110α) signaling contributes to the development of diabetic cardiomyopathy, and elevated PI3K(p110α) signaling protects against adverse remodeling including diastolic dysfunction, fibrosis and apoptosis. The mechanisms underlying this protection are not completely understood. We recently proposed a potential mechanism, by which PI3K(p110α) inhibits high glucose-induced activation of PKCβ, NADPH, ROS and the MAPK apoptosis signal-regulating kinase 1, as well as maintaining Akt activation and possibly enhancing mitochondrial function (Ritchie et al., 2012). 4. Conventional therapies for treatment of diabetic cardiomyopathy 4.1. Glycemic control Hyperglycemia can directly impair biological processes important for the maintenance of normal cellular function, including lipid metabolism, calcium homeostasis, redox signaling, and substrate supply and utilization. Logically, control of blood glucose levels is central to the management of diabetes and associated complications. Indeed, numerous large epidemiological studies in the 1990s reported convincing positive associations between the level of glycemic control and reduced incidence of cardiovascular disease, which remains relevant today (Kuusisto et al., 1994; Hanefeld et al., 1996; Turner et al., 1998; Iribarren et al., 2001; Held et al., 2007). A 1% rise in HbA1c is associated with an 11% increased risk of cardiovascular mortality, from the UK Prospective Diabetes Study (UKPDS) (Stratton et al., 2000). More recent studies have also suggested that tight glycemic control is beneficial for the preservation of normal LV diastolic function in the early stages of diabetes (von Bibra et al., 2004; von Bibra et al., 2007). However, despite the current era of intensive glucose-lowering therapies, the cardiac complications of diabetes often remain inadequately managed (Yong et al., 2007). Even so, several prominent, highly-cited prospective randomized clinical trials have recently failed to demonstrate improved cardiovascular prognosis with aggressive glycemic control. For example, although intensive glycemic control could be achieved in a large cohort of more than 5000 T2DM patients in the ACCORD (Action to Control Cardiovascular Risk in Diabetes) trial, this was actually associated with increased all-cause mortality compared to the standard glucoselowering therapy cohort, without any cardiovascular benefits (Gerstein et al., 2008). A similar lack of cardiovascular benefit was reported in the subsequent, longer-duration VADT (Veterans Affairs Diabetes Trial),

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after N5 years follow-up (Duckworth et al., 2009). The effectiveness of current anti-diabetic therapies has been widely reviewed elsewhere (Krentz & Bailey, 2005). In general, metformin remains the drug of choice for glycemic control in T2DM patients (Krentz & Bailey, 2005; Anfossi et al., 2010); cardiac and vascular benefits may accompany its well-established antidiabetic actions. Sulfonylureas such as glyburide and gliclazide block ATP-sensitive K+ channels to elicit insulin secretory actions in pancreatic β-islet cells. This class of glucose-lowering drugs has been used for the treatment of T2DM for over 50 years (Krentz & Bailey, 2005), but may be linked to increased risk of cardiac death in patients with ischemic heart disease (Tzoulaki et al., 2009). Two newer classes of anti-diabetic compounds, thiazolidinediones (TZDs) and most recently the incretin-based therapies, have been rapidly incorporated into clinical practice. Due to their potent antihyperglycemic effects and their emerging role in the improvement of cardiovascular outcomes, we review them below. 4.2. Thiazolidinediones (TZDs) TZDs target PPARγ (see Section 3.2). The first TZD was approved to lower blood glucose in T2DM in 1997 [see (McGuire & Inzucchi, 2008)]. TZDs are effective in lowering blood glucose levels by improving insulin sensitivity in fat, muscle and liver cells. Animal studies demonstrate that TZDs improve glucose metabolism via increased expression and function of glucose transporters in the heart (Young, 2003). Based on clinical trials and animal studies, TZDs also inhibit systemic inflammation, favorably affect endothelial function and blood pressure, inhibit cardiac hypertrophy and collagen accumulation, and improve LV diastolic function (Tsuji et al., 2001; Asakawa et al., 2002; McGuire & Inzucchi, 2008; von Bibra et al., 2008; Ordu et al., 2010). However, despite these protective properties, major drawbacks associated with the use of TZDs include weight gain, peripheral edema, and the possible increased risk of HF (due to fluid retention due to increased renal retention of sodium). Of note, some TZDs (e.g. troglitazone and muraglitazar) were removed from the market or failed to achieve regulatory approval due to toxicity and/or adverse cardiovascular events (Loke et al., 2011). Due to the potential risk of HF (Wooltorton, 2002; Delea et al., 2003; Kermani & Garg, 2003; Home et al., 2007; Loke et al., 2011), the use of current TZDs (rosiglitazone and pioglitazone) is not recommended for patients with New York Heart Association functional class III or IV HF (Nesto et al., 2003). 4.3. Incretin-based therapies Glucagon-like peptide-1 receptor (GLP-1R) agonists and dipeptidyl peptidase-4 (DPP4) inhibitors are relatively new drugs approved for the treatment of T2DM. Exendin-4 (GLP-1R agonist) was approved for the treatment of T2DM in the United States in 2005, and the first DPP4 inhibitor (sitagliptin) was approved in 2006 [see (Drucker et al., 2010)]. Incretin-based agents exert their actions through potentiating signaling through the incretin receptor. Incretins (e.g. GLP-1 and glucose-dependent insulinotropic peptide) are derived from the gut, and secreted at low levels in the fasting state. GLP-1 stimulates insulin secretion in a glucose-dependent manner via its actions on pancreatic β-islet cells (Edvell & Lindstrom, 1999; Farilla et al., 2003). Following food intake, circulating incretin levels rapidly increase but then decrease due to renal clearance and degradation by DPP4. Degradationresistant GLP-1R agonists and DPP4 inhibitors have been developed to overcome the short circulating half-life of incretins. Sustained GLP-1R activation (via GLP-1R agonists or DPP4 inhibitors) controls blood glucose via regulation of islet function (stimulation of insulin secretion and inhibition of glucagon secretion) (Drucker et al., 2010). The advantage of incretin-based therapies in treating diabetes is the glucose-dependent mechanism underlying insulin-secretion by GLP-1R activation, thereby reducing the risk of hypoglycemia. GLP-1R activation with GLP-1R agonists is also associated with weight loss, due to its

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ability to inhibit gastric emptying and reduce food intake (Cho et al., 2012). In addition, a growing body of evidence suggests that GLP-1 may have cardioprotective actions in addition to its main role in glycemic regulation. The GLP-1R is expressed in a wide range of tissues including the heart (Thorens, 1992). GLP-1 is thought to enhance insulin sensitivity and promote glucose uptake in the myocardium, which may translate to improved cardiac efficiency and function (Grieve et al., 2009). Transgenic mice with genetic deletion of GLP-1Rs display elevated LVEDP at 2 months of age, and pathological LVH by 5 months of age, compared to wildtype controls (Gros et al., 2003), suggesting that GLP-1 may play a critical role in the regulation of cardiac structure and function. GLP-1 mediates protection against cardiac dysfunction and injury following MI, both in experimental models (Noyan-Ashraf et al., 2009; Timmers et al., 2009) and in patients (Nikolaidis et al., 2004b). The role of GLP-1 in the prevention of HF is also gaining increasing attention. Both short-term and chronic infusion of GLP-1 exert protection against LV contractile dysfunction, and increase myocardial insulin sensitivity and glucose uptake in experimental settings of dilated cardiomyopathy and HF (Nikolaidis et al., 2004a; Poornima et al., 2008). Preliminary studies in patients with chronic HF have also implicated a protective role of GLP-1 in improving systolic function (Sokos et al., 2006). Further longer-term studies to confirm this association between GLP-1 and improved cardiovascular outcomes are required. The longerterm impact of GLP-1 agonists and DPP4 inhibitors on both diabetesinduced cardiac remodeling and dysfunction that characterize diabetic cardiomyopathy, and subsequent risk of heart failure death, in large diabetic patient populations is still considered a work-in-progress. However given the ability of GLP-1R agonists to lower blood glucose, promote weight loss, and potentially provide cardiac protection, these agents are currently one of the most promising drugs for the dual treatment of diabetes and cardiovascular disease. Promising cardioprotective actions of incretin-based therapies specifically in the setting of diabetes have already been observed in a number of pre-clinical studies (e.g. Connelly et al., 2013; Hausenloy et al., 2013). Of note however, two possibly rare but potential safety issues include pancreatitis and medullary thyroid cancer (Drucker et al., 2010). Moreover, negative findings were recently reported for saxagliptin, in which HF tended to increase (Scirica et al., 2013). Whether this is specific to saxagliptin, or will emerge as a class effect of the dipeptidyl peptidase-4 inhibitors (which also block degradation of other hormones in addition to GLP1) remains to be resolved. GLP-1R agonists may thus prove more favorable than inhibition of DPP4. 4.4. β-Blockers β-adrenoceptor blockers are a class of antihypertensive antiarrhythmic agents with additional antiischemic and antiatherogenic properties. Their use for the management of hypertension, MI and cardiac arrhythmias in the general population has been well-established for several decades (Wikstrand, 1990; Olsson et al., 1992; Gottlieb et al., 1998; Lopez-Sendon et al., 2004), particularly where there is concomitant coronary artery disease (Chalmers et al., 2013). As recently reviewed, βblockers remain highly-regarded for the management of HF (Bristow, 2011; Koitabashi & Kass, 2012). Considerable historical clinical evidence favors the use of β-blockers in the diabetic population, with benefits observed at the level of cardiac morbidity and mortality in diabetic patients with concomitant hypertension, coronary disease and after MI (Kjekshus et al., 1990; Jonas et al., 1996; Gottlieb et al., 1998). In diabetic patients, there are strong indications that tight control of blood pressure translates to reduced cardiovascular events; intensive blood pressure-lowering with β-blockers reduces macrovascular and microvascular events in this population, with similar efficacy to ACE inhibitors (ACE-Is) (Stearne et al., 1998). β-blockers have been observed to increase the risk of development of new diabetes in non-diabetic hypertensive patients, in contrast to ACE-Is and calcium antagonists which do not (Gress et al., 2000). Further, increases in FPG can be observed

with non-selective (but not β1-selective) β-blocker use (WilliamOlsson et al., 1979; Cruickshank, 2002; Landray et al., 2002). As a result, there is the risk that β-blockers may be under-utilized in diabetic patients, despite convincing, favorable mortality data for their use in diabetic patients post MI (Malmberg et al., 1989; Kjekshus et al., 1990). β-blockade, particularly with newer agents such as carvedilol, elicits beneficial effects in diabetic patients on both cardiac and systemic metabolism, switching to myocardial glucose utilization (lowering myocardial oxygen consumption) with maintained or even improved glycemic control (Reaven et al., 1996; Bell, 2003; Messerli & Grossman, 2004; Wai et al., 2012). Given the cardioprotection afforded by βblockade in diabetic patients with concomitant hypertension and/or post MI, any reluctance for its use in managing cardiovascular events in diabetic patients is considered unwarranted, with clinical need likely outweighing minimal risks (Cruickshank, 2002; Landray et al., 2002). The availability of newer β-blockers, with favorable tolerability and improved metabolic profiles compared with the first and second generation agents warrants their consideration for the treatment of HF even where diabetes is evident. 4.5. Calcium channel blockers Similar to β-blockers, calcium channel blockers are commonly used for the clinical management of hypertension, angina pectoris and cardiac arrhythmias in the general population. Major randomized clinical trials suggest that their beneficial effects on cardiac mortality and other cardiovascular endpoints are preserved or even enhanced in the diabetic population, in both European (Tuomilehto et al., 1999) or Chinese patient cohorts (Wang et al., 2000). Calcium channel blockers are reported to offer slight benefit over ACE-Is for prevention of stroke in diabetic patients, whereas ACE-Is may be more efficacious in the prevention of other cardiovascular events such as MI and HF (Nosadini & Tonolo, 2002). Importantly, calcium channel blockers do not increase risk of the development of new diabetes in non-diabetic hypertensive patients (Gress et al., 2000). The impact of calcium channel blockers on glycemic control warrants further investigation. Experimental evidence suggests that the calcium channel blocker verapamil improves glucose homeostasis and insulin sensitivity, perhaps as a result of downregulation of pro-apoptotic TxNIP expression in pancreatic β-islet cells (Xu et al., 2012). Calcium channel blockers are frequently administered in combination with ACE-Is in diabetic hypertensive patients (Chalmers et al., 2013); the net effect of this combination therapy on development and treatment of diabetic cardiomyopathy remains however to be fully resolved. 4.6. Lipid-lowering therapies Irregularities in circulating lipid profiles are considered to play a major role in the pathogenesis of atherosclerosis; this remains the case in diabetic patients, where cardiovascular risk is increased. The 3hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (known as statins) represent the most commonly-prescribed class of lipid-lowering therapy; their efficacy is well-established in both diabetic and non-diabetic patients (Colagiuri & Best, 2002). A meta-analysis of 14 prospective clinical studies reveals that the proportion of major coronary events (non-fatal MI or ischemic heart disease death), as well as coronary revascularization and stroke, are reduced by ≥20% by statin treatment with every 1 mmol/L reduction in low density lipoprotein (LDL) cholesterol (Baigent et al., 2005), regardless of whether the total patient group or just the diabetic cohort were studied. The Heart Protection Study demonstrated a similar reduction in major cardiovascular events over 5 years with daily simvastatin treatment in diabetic patients without pre-existing coronary disease (Collins et al., 2003). The PPARα fibrate agonists are also used to improve high density lipoprotein (HDL)-cholesterol and lower LDL-cholesterol and triglyceride profiles, in diabetic and non-diabetic patients alike, with meta-

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analysis of N50 prospective clinical trials affirming their efficacy in this regard (Birjmohun et al., 2005). Further meta-analysis restricted to T2DM indicated that coronary events are reduced by fibrate lipidlowering treatment (Allemann et al., 2006). Although diabetes is associated with increased cardiovascular risk, there is evidence that fibrate therapy may confer a greater relative risk reduction in cardiovascular events in diabetic than non-diabetic patients, on the composite endpoint of death from coronary heart disease, MI and stroke (Rubins et al., 2002). As suggested from the ACCORD lipid trial however, there is no additional benefit in combination statin-fibrate therapy on cardiovascular events compared to statin therapy alone (Ginsberg et al., 2010). Thus, aggressive treatment of lipid abnormalities (by any means), in addition to intensive glycemic and blood pressure control, appears important for long-term health outcomes in diabetic patients. 4.7. Angiotensin converting-enzyme inhibitors Due to the importance of the RAAS in the regulation of blood pressure (refer to Section 2.1), ACE-Is were first developed as a therapeutic agent for the treatment of hypertension. ACE-Is have been utilized for more than two decades as first-line therapy for this and several other clinical indications, including congestive HF, LV dysfunction, atherosclerosis and the majority of diabetic vascular complications (Brown & Vaughan, 1998; Jandeleit-Dahm et al., 2005; Calcutt et al., 2009). RAAS blockade is beneficial in treating these complications, with ACE-Is and subsequently-developed AT1 angiotensin receptor blockers (ARBs) and aldosterone antagonists comprising commonly used RAAS inhibitors (Sander et al., 1999; Timmermans, 1999; Maron & Leopold, 2010). Intriguing roles for the more recently-described member of the RAAS, ACE-2 (which generates the Ang-(1–7) peptide), as well as other Ang peptides and receptors are now emerging [see (Iwata et al., 2011; W. Wang et al., 2012; Burrell et al., 2013; Ohishi et al., 2013)], these are however not yet realized as clinically-available pharmacotherapies. As ACE-Is remain the “gold standard” for the management of the cardiovascular complications of diabetes, a more detailed review of their mechanism and effectiveness is provided here. 4.7.1. Mechanism of action and pharmacology of angiotensin converting-enzyme inhibitors ACE is also known as kininase II, because in addition to cleavage of Ang I to Ang II, ACE catalyses degradation of the physiologicallyactive peptide bradykinin, which promotes vasodilation via release of endothelial-derived NO•, prostacyclin, and endothelium-derived hyperpolarizing factor (Zusman, 1987). Bradykinin-triggered natriuresis contributes further falls in blood pressure. ACE thus regulates vascular tone by two mechanisms, prevention of vasodilation by bradykinin, and promotion of vasoconstriction by increased Ang II signaling. ACE inhibition hence elicits dose-dependent reduction in Ang II levels, with concomitant inhibition of bradykinin degradation and lowering of systolic and diastolic pressure (Dunn et al., 1984; Erdos et al., 1999; Wong et al., 2004). The pharmacokinetic profiles of different ACE-Is are distinguished by their biochemical structure and bioavailability, plasma half-life, elimination profile and their distribution and affinity for tissue-bound ACE (Brown & Vaughan, 1998; Wong et al., 2004). As reviewed by Wong et al., ACE-Is can be divided into 3 subgroups, based on the molecular structure of their active moieties; sulfydryl-containing, dicarboxylcontaining and phosphorus-containing (Wong et al., 2004). While ACE-Is are widely-regarded as the “gold standard” for management of many cardiovascular/renal disorders, their potential for (largely irritating rather than life threatening) side effects may result in discontinuation of therapy, which is often substituted with ARBs (Lombardi et al., 2005). The most common side effect is cough, occurring in 15–30% of patients, which is attributed to increased bradykinin levels (Israili & Hall, 1992; Overlack, 1996). Angioedema, likely also a secondary consequence of bradykinin accumulation, is reported in ~0.1–0.2% of patients

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(Slater et al., 1988; Abdi et al., 2002; Lombardi et al., 2005). Angioedema is characterized by swelling of the lips, tongue, nose, throat and other localized areas on the face; while uncommon, it is potentially lifethreatening. ACE-I use also needs to be carefully monitored in the elderly, or individuals with HF who are susceptible to hypotension; dosages are usually reduced in these patients (Wong et al., 2004). In patients with impaired kidney function or reduced renal blood flow, hyperkalemia is another potential side effect of ACE-I usage. Diabetic patients with uncontrolled glucose and renal tubular acidosis are at particular risk for hyperkalemia (Izzo & Weir, 2011), which can be further exacerbated when ACE-Is are used concomitantly with ARBs, aldosterone blockers, potassium supplements, or sodiumrestricted diets (Izzo & Weir, 2011). A further contraindication to ACE-I therapy is pregnancy, due to the potential for fetal defects including pulmonary hypoplasia, growth retardation, and possible death if administered in the second or third trimester (Pryde et al., 1993; Sedman et al., 1995). 4.7.2. The role of renin–angiotensin–aldosterone system blockade via angiotensin converting-enzyme inhibitors in prevention of diabetic and cardiovascular complications Despite their original development for the treatment of hypertension, ACE-Is are now routinely utilized for the management of congestive HF, coronary artery disease and renal failure. In addition, several studies have also suggested that ACE-Is are able to reduce the incidence of T2DM in patients with hypertension and HF (Vermes et al., 2003; Padwal & Laupacis, 2004; Gillespie et al., 2005; Jandeleit-Dahm et al., 2005). 4.7.2.1. Angiotensin converting-enzyme inhibitors and cardiovascular disease. Hypertension is a significant cardiovascular risk factor; over a decade ago, this was shown to confer significant reductions in the incidence of HF (by 50%), stroke (by a 35–40%), and MI (by 20–25%) when well-controlled (Neal et al., 2000). By maintaining the balance between Ang II and bradykinin, the RAAS plays a critical role in blood pressure regulation; its overactivation may be considered a significant cardiovascular risk factor in hypertensive patients. As a result, ACE-Is are first-line therapy for the treatment of hypertension in patients with congestive HF, stroke, diabetes, renal failure, after MI or in the elderly (Chobanian et al., 2003; Wing et al., 2003; Hsueh & Wyne, 2011). The RAAS modulates MI both acutely while it is still evolving (considered an adaptive response to preserve blood pressure and perfusion) and following recovery [in which prolonged activation is detrimental to cardiac function (Remes, 1994)], where inadequate oxygen delivery to the myocardium may be exacerbated by Ang II-induced vasoconstriction, exaggerating myocardial injury. The potential benefits of ACE-I therapy subsequent to MI has been the focus of several major clinical trials. In the Survival and Ventricular Enlargement (SAVE) and Trandolapril Cardiac Evaluation (TRACE) studies, ACE-I intervention commencing several days after the acute insult is associated with a ~30% reduction in mortality compared to placebo in patients with LV systolic dysfunction post MI (Rutherford et al., 1994; Kober et al., 1995). Meta-analysis of several studies performed by the ACE Inhibitor MI Collaborative Group reported that ACE-I is associated with a 7% reduction in mortality in the first 30 days after MI, corresponding to 5 lives saved for every 1000 patients treated (Franzosi et al., 1998). Dysregulation of major neurohormonal systems, including the sympathetic nervous system and the RAAS, has been recognized for many years as integral to the development and progression of HF (Packer, 1992). The RAAS is also thus an important therapeutic target in this context, as demonstrated by several large, randomized, placebocontrolled trials. ACE-Is increase survival rates in patients even with severe congestive HF, where systolic dysfunction is particularly marked. The Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS) trial was the first to identify a link between ACE-I and reduced mortality in patients with severe systolic HF, reporting a 40% decrease in mortality after 6 months of enalapril therapy (Swedberg, 1987).

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These observations were further supported by the SOLVD study, in which ACE-I also reduced the incidence of HF and hospitalization in addition to mortality, in patients with LV ejection fraction b30% (Yusuf, 1991; Nicklas et al., 1992). Given that intracellular Ang II generation can occur independent of the circulating RAAS (Singh et al., 2008b), therapeutic strategies that inhibit both extracellular and intracellular RAAS signaling concomitantly may offer optimal protection against cardiovascular events. Both experimental and clinical studies have demonstrated benefits in treating LVH with ACE-Is (Vaughan & Pfeffer, 1994; Gray et al., 1998; Gagnon et al., 2004; He et al., 2005; Brower et al., 2007; Ruggenenti et al., 2008). In rodent models of cardiac remodeling post MI, pressureoverload or volume-overload, ACE-I treatment reduces LV volumes and LV filling pressure, with concomitant improvement in adverse structural LV remodeling (Pfeffer et al., 1985; Gagnon et al., 2004; Brower et al., 2007). Attenuation of LV enlargement with long-term ACE-I therapy is also associated with improved survival. Evidence also suggests that ACE-Is regress pathological LVH to a greater degree than other antihypertensive therapies; meta-analysis of 39 clinical studies indicated a 13% reduction in LV mass with ACE-Is, significantly greater than that achieved with calcium channel blockers (9%), diuretics (7%) and β-blockers (6%) (Schmieder et al., 1996; Klingbeil et al., 2003). The mechanism of ACE-I reversal of LVH is likely a combination of their antihypertensive properties (Dunn et al., 1984; Erdos et al., 1999; Wong et al., 2004), and removal of the trophic and pro-oxidant effects of Ang II on vascular smooth muscle (Klingbeil et al., 2003) and cardiomyocytes (Sadoshima & Izumo, 1993; Sadoshima et al., 1993; Timmermans et al., 1993; Ritchie et al., 1998a; Laskowski et al., 2006), in addition to potentiation of the antihypertrophic effects of bradykinin (Ritchie et al., 1998a; Rosenkranz et al., 2000, 2002). 4.7.2.2. Angiotensin converting-enzyme inhibitors for management of diabetic complications. ACE-Is are widely used in patients with cardiovascular disease who are at high risk of developing T2DM, due to the potential added benefits of improving insulin sensitivity and resistance. Several independent trials have suggested that agents blocking RAAS activation, including ACE-Is, are able to prevent or delay the onset of diabetes. The Captopril Prevention Project (CAPPP) reported a 30% reduction in the rate of new-onset diabetes with ACE-I compared to patients receiving conventional diuretic and/or β-blocker-based therapy, when correcting for age, glucose, body mass index, circulating hemoglobin and systolic blood pressure (Niklason et al., 2004). The Heart Outcomes Prevention Evaluation (HOPE) trial reaffirmed the role of ACE inhibition in preventing the onset of diabetes through observations that ACE-I reduced the incidence of diabetes in high-risk individuals (Yusuf et al., 2001). In the placebo group, 5.4% of patients had developed T2DM within the 4.5 year duration of the study, compared to only 3.6% of patients in the ramipril group. Similar observations were obtained in the 2nd Australian National Blood Pressure study (ANBP-2), where ACE-I treatment was associated with a 31% risk reduction in the incidence of new-onset diabetes in elderly patients, compared with diuretic treatment (Reid et al., 2003). Retrospective analysis of a subgroup of participants in the SOLVD trial also demonstrated the ability of ACE-I to reduce the incidence of diabetes in patients with LV dysfunction, to ~6% over the 3-year study, compared to 22% with placebo (Vermes et al., 2003). The ability of RAAS blockade to improve peripheral insulin sensitivity and glucose metabolism is a likely contributing mechanism underlying ACE-I protection against the development of diabetes in patients. The fall in the incidence of new-onset diabetes with ACE-I treatment was usually accompanied by an improvement in glycemic control. The HOPE study reported a significant reduction in HbA1c in ramipril-treated diabetic patients (Gerstein et al., 2000). In the UKPDS, patients randomized to receive captopril treatment had lower levels of HbA1c compared to patients on β-blocker or diuretic therapy (Stearne et al., 1998). This is consistent with findings in the Study to Evaluate Carotid Ultrasound changes in patients treated with vitamin E (SECURE) trial, where fasting glucose levels were higher in placebo-treated control patients (15.8 mg/dL)

compared with ramipril-treated patients (9.6 mg/dL) (Lonn et al., 1999). Hypertensive patients have an increased propensity to develop T2DM (Gress et al., 2000; Sowers & Bakris, 2000); indeed, a large proportion of hypertensive subjects experience a degree of glucose intolerance, where an amplified plasma insulin response consistently takes place following a glucose load (Defronzo & Ferrannini, 1991). Several mechanisms have been suggested to explain this phenomenon. Alterations in the composition of skeletal muscle (enhanced number of slow-twitch insulin-sensitive muscle fibers), and/or changes in skeletal muscle vasculature (e.g. increased vasoconstriction, which diminishes delivery of glucose and insulin to skeletal muscle), may contribute to impaired glucose tolerance (for review, see (McFarlane et al., 2003)). In addition, abnormalities in signaling kinases downstream of the insulin receptor (e.g. changes in PI3K/Akt signaling induced by high glucose) may also result in reduced glucose sensitivity (Macfarlane et al., 1997). Interruption of the RAAS via ACE-Is use improves insulin signaling and reduce insulin resistance in hypertensive, non-diabetic and T2DM patients, likely via at least two separate mechanisms (Paolisso et al., 1992). ACE-I affords beneficial effects on the microcirculation by reducing Ang II-mediated vasoconstriction and enhancing capillary density, increasing perfusion to skeletal and cardiac muscle, as well as to pancreatic β-islet cells. As a result, glucose uptake and insulin delivery are likely improved (Henriksen & Jacob, 2003; Bomfim & Mandarim-de-Lacerda, 2005; Sabino et al., 2008; Hiller et al., 2010). Considerable experimental and clinical evidence suggests a role for ACE-I in preventing cardiovascular disease. Importantly, this includes protection against diabetes-related microvascular and macrovascular complications. The Microalbuminuria, Cardiovascular and Renal Outcomes (MICRO) HOPE substudy demonstrated that ACE-I lower risk of cardiovascular outcomes in high-risk diabetes patients (Gerstein et al., 2000), including MI (by 22%), stroke (by 33%), cardiovascular death (by 37%) and total mortality (by 24%). This is consistent with the observations from the CAPPP study, in which ACE-Is reduced the combined risk of MI, stroke, and sudden death in diabetic patients, as well as risk of a cardiac event (Hansson et al., 1999). The ACE-I ramipril also effectively prevents diabetic cardiomyopathy in preclinical models of both T1DM and T2DM (Huynh et al., 2012, 2013). Thus, where side effects do not preclude the use of ACE-Is, they represent attractive pharmacotherapy for managing the vascular and cardiac complications of diabetes. Given that up to 20% of diabetic patients do not tolerate ACE-Is, and that even the most effective regression of LV remodeling and dysfunction usually never completely restores the myocardium to normal full health, alternative approaches for managing diabetic cardiomyopathy (as stand-alone or complimentary to standard care) are thus required. 5. Early evidence favoring antioxidants for treatment of diabetic cardiomyopathy As discussed in Section 2.2, an increasing number of studies have demonstrated the pivotal role of oxidative stress, and reduced endogenous antioxidant capacity, in the pathophysiology of HF and/or diabetes. Antioxidants have thus been proposed as a possible therapeutic strategy for the treatment of diabetic cardiomyopathy and other cardiac pathologies. The relative efficacy of conventional antioxidant approaches including SOD isoforms, catalase, GPx, Trx and vitamins C and E are now discussed. 5.1. Superoxide dismutase-based approaches SOD-based therapies elicit beneficial effects in various experimental models of diabetic and/or cardiac pathology. Targeted transgenic CuZnSOD expression in pancreatic β-islet cells significantly attenuates alloxan-induced increases in blood glucose levels in vivo (Kubisch et al., 1997). In cultured mesangial cells, AdV-CuZnSOD transfection prevents the high glucose-induced stimulation of collagen synthesis

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in vitro (Craven et al., 2001). SOD-based therapies also offer protection from I-R injury and chronic HF (Ambrosio et al., 1986; Salvemini et al., 2002). However, in vivo exogenous SOD administration is limited by the large size of SOD isoforms (restricting cell permeability) and short half-life (Salvemini et al., 2002). To overcome this, various SOD mimetics with lower molecular mass have been developed. SOD mimetic-based approaches have been examined in two animal models of pre-diabetic insulin-resistance, fructose-feeding and cardiacselective deletion of GLUT4 expression. In the setting of systemic insulin resistance, the hydrophilic, low molecular weight nitroxide tempol (4-hydroxy-2,2,6,6 tetramethylpiperidine-N-oxyl) blunts the high fructose diet exacerbation of pressure-overload hypertrophy and associated LV lipid peroxidation and systolic dysfunction (Chess et al., 2008). Tempol elicits similar preservation of myocardial structure in the cardiac insulin-resistant GLUT-4-deficient mouse, across cardiac index, pro-hypertrophic and pro-fibrotic gene expression, with blunted cardiac upregulation of the NADPH oxidase Nox2 and Nox1 subunits (Ritchie et al., 2007). Cardiac-specific transgenic MnSOD expression similarly limits cardiac remodeling in T1DM mice, accompanied by improved cardiac function and protection of cardiac mitochondria (Shen et al., 2006). 5.2. Catalase- and glutathione peroxidase based approaches In experimental settings of diabetic cardiomyopathy, overexpression of catalase improves cardiac morphology, mitochondrial structure and myofibrillar substructure, as well as cardiomyocyte contractility (Ye et al., 2004), associated with a significant reduction in ROS levels. Furthermore, cardiac-specific overexpression of catalase similarly improves cardiomyocyte contraction, and blunts the increase in ROS generation and apoptosis in STZ diabetic mice (Turdi et al., 2007). Transfection of cell lines has been frequently used to examine the role of GPx in the prevention of oxidative stress. Overexpression of GPx1 in vitro has been shown to protect both pancreatic β-islet cells and human endothelial cells against ROS-induced damage and death (Faucher et al., 2005; Harmon et al., 2009). Overexpression of GPx1 specifically in the pancreatic β-islet cells of db/db mice delays the progression of hyperglycemia, and by 20 weeks of age, their blood glucose levels are not different to their non-diabetic counterparts (Harmon et al., 2009). Moreover, GPx1 transgenic diabetic mice exhibit improved LV diastolic function, which is accompanied by the attenuation of cardiomyocyte hypertrophy, cardiac fibrosis and apoptosis, compared to non-transgenic diabetic controls (Matsushima et al., 2006). Catalase- and GPx based approaches thus offer some benefit in animal models of diabetic cardiomyopathy. 5.3. Thioredoxin-based approaches There is evidence that pancreatic β-cells-directed transgenic Trx expression attenuates the development of diabetes in response to STZ, suggesting that Trx protects against the destruction of pancreatic β-islet cells (Hotta et al., 1998). Turning to cardiac pathologies, overexpression of Trx in mice in vivo reduces the degree of cardiac hypertrophy, fibrosis, apoptosis and oxidative stress in response to pressureoverload or MI, with preservation of LV systolic function and capillary density (Yamamoto et al., 2003; Adluri et al., 2011). Taking these findings into the diabetic context, the exaggerated response to MI in diabetic rats, across cardiac remodeling, apoptosis and capillary density, is attenuated by AdV-Trx1 administration immediately post MI, with protection of both systolic and diastolic function (Samuel et al., 2010). Preliminary evidence also suggests that Trx-transgenic mice may also be protected from diabetic cardiomyopathy, even in the absence of MI (Peter et al., 2006). Although the therapeutic potential of recombinant Trx for managing cardiac pathologies has been postulated (Matsushima et al., 2011), its efficacy for managing diabetic cardiomyopathy remains an intriguing but unresolved possibility.

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5.4. Vitamin C and Vitamin E-based approaches The efficacy of supplementary therapy with non-enzymatic antioxidant micronutrients such as vitamin C, E and zinc (over and above their normal dietary intake) in preventing the development of cardiovascular complications in diabetic patients has received considerable attention by clinical researchers. Overall, the results have been largely disappointing, failing to offer clear cardiovascular benefit (Yusuf et al., 2000; Sesso et al., 2008). Firstly, the potential of vitamin C supplementation to treat pathophysiologies specifically related to hyperglycemia has been examined (Ting et al., 1996; Cunningham, 1998; Afkhami-Ardekani & Shojaoddiny-Ardekani, 2007; Dakhale et al., 2011). Diabetic patients supplemented with high dose (1 g) daily vitamin C exhibited a reduction in fasting blood sugar, triglycerides, total cholesterol, LDL, HbA1c and serum insulin (Afkhami-Ardekani & Shojaoddiny-Ardekani, 2007). Vitamin C, administered in conjunction with metformin therapy, also improved fasting and post-meal glucose levels and HbA1c compared with metformin and placebo treatment (Dakhale et al., 2011). In addition to these reported benefits in glycemic control, vitamin C has also been shown to improve diabetes-associated cardiovascular complications, at least at the level of endothelial vasodilator function in diabetic patients (Ting et al., 1996; Wold & Ren, 2004). While these smaller studies have observed a beneficial effect of vitamin C supplementation on diabetes (and to a lesser extent on its associated complications), larger studies not restricted to just the diabetic population have generally failed to yield similar benefits with vitamin C intake (Rimm et al., 1993; Sahyoun et al., 1996). The clinical evidence favoring vitamin C supplementation is thus weak at best. The potential for vitamin E to elicit favorable effects on heart disease and diabetes, by reducing oxidative stress, has been similarly examined. Vitamin E in some studies reduced the risk of coronary disease, atherosclerosis and mortality (Rimm et al., 1993; Sahyoun et al., 1996; Stephens et al., 1996; Munteanu et al., 2004). Specifically examining its impact in the diabetic context, epidemiological studies report low plasma vitamin E concentrations increasing risk of developing both T1DM and T2DM (Salonen et al., 1995; Knekt et al., 1999). It is thus possible that maintaining a normal dietary intake of vitamin E may play a protective role in the development of both diabetes and heart disease. Evidence from animal models suggests that vitamin E supplementation significantly reduces cardiac apoptosis, lipid peroxidation and protein oxidation, in addition to preserving cardiac function (Shirpoor et al., 2009). Despite these promising results, available clinical data questions the true efficacy of supplementary vitamin E therapy in patients at risk of, or affected by, cardiovascular disease and/or diabetes, either showing no benefit (Yusuf et al., 2000; Morris & Carson, 2003; Vivekananthan et al., 2003; Lonn et al., 2005; Liu et al., 2006; Suksomboon et al., 2011) or possibly even associated with potential adverse effects. Although these studies may not have been sufficiently powered to detect such events, there are reports of increased risk of HF (Lonn et al., 2005) and all-cause mortality (Miller & Guallar, 2009), particularly at high doses of vitamin E supplementation. Further, large, wellcontrolled prospective studies indicate that vitamin E does not reduce risk of developing T2DM or exhibiting a cardiovascular event (Yusuf et al., 2000; Liu et al., 2006). Importantly however, vitamin E is considered a relatively weak antioxidant (and may even possess some prooxidant properties) (Miller & Guallar, 2009), and unlike more potent antioxidants such as tempol, requires electron donation following a single interaction with a ROS (Vivekananthan et al., 2003; Rasoli et al., 2011). In summary, clinical evidence thus does not favor the use of vitamin C or E supplementation as a “pharmacotherapy” to prevent or manage diabetes or its cardiovascular complications (as distinct from the detrimental health effects of diets deficient in these vitamins). Of the above antioxidant approaches, both vitamin C and E are readily available, and offer ease of administration, for human use (perhaps explaining their popularity in the above clinical studies). Much of the disappointment

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around the perceived failure of antioxidant approaches to offer therapeutic benefits in cardiovascular disease can thus likely be attributed to the above findings. As discussed however, both are relatively weak antioxidants, and generate a radical species as part of their actions. Given the convincing evidence for a causal role of ROS in the cardiac and multiple other complications of diabetes, clinical studies examining the clear therapeutic promise of more potent antioxidant approaches than vitamins C and E are warranted. 6. Novel therapies offering new promise for diabetic cardiomyopathy 6.1. Coenzyme Q10 supplementation In contrast to the limitations of vitamins C and E as antioxidant approaches in cardiovascular disease, there are several favorable studies exploiting the antioxidant properties of the mitochondrial electron carrier coenzyme Q10 to rescue cardiovascular disease, both in preclinical (Nakamura et al., 1982; Okamoto et al., 1991; Maulik et al., 2000) and clinical settings (Soja & Mortensen, 1997; Langsjoen & Langsjoen, 1999; Rosenfeldt et al., 2007; Chew et al., 2008; Judy et al., 1991; Serra et al., 1991; Langsjoen et al., 1997; Singh & Niaz, 1999; Molyneux et al., 2008; Kumar et al., 2009), free of adverse effects. Indeed, the past 40 years has seen a steady increase in the number of publications focused on coenzyme Q10 and its efficacy in reducing cardiomyopathy, hypertension and ischemic damage. As reviewed previously, a likely mechanism by which coenzyme Q10 supplementation elicits cardioprotection is maintenance of cardiomyocyte cellular (and particularly mitochondrial) function (Langsjoen & Langsjoen, 1999; Kumar et al., 2009). Coenzyme Q10 has also been shown to lower both FPG and systemic oxidative stress, as well as enhance HDL levels (Singh & Niaz, 1999). Evidence from several placebo-controlled clinical trials indicates that three quarters of patients with cardiovascular disease exhibit improvements in both cardiac output and stroke volume; importantly, enhanced ejection fraction is evident in the majority of patients studied (Soja & Mortensen, 1997). The frequency of angina attacks is reduced and exercise tolerance enhanced (Serra et al., 1991). A meta-analysis of 12 clinical trials observed reductions in systolic and diastolic blood pressure of 17 and 10 mmHg, respectively, in hypertensive patients treated with coenzyme Q10 (Rosenfeldt et al., 2007), perhaps at least in part due to its ROS-scavenging properties, improving NO• bioavailability and hence vascular tone. In patients with more severe disease (hypertrophic cardiomyopathy or HF), coenzyme Q10 improves LV wall thickness and diastolic function, as well as long-term survival (Judy et al., 1991; Langsjoen et al., 1997; Molyneux et al., 2008; Kumar et al., 2009). Pre-operative coenzyme Q10 may also afford protection against myocardial injury in patients undergoing cardiac surgery, increasing myocardial and LV mitochondrial coenzyme Q10 levels, enhancing mitochondrial efficiency and improving ischemic tolerance (Rosenfeldt et al., 2005). Coenzyme Q10 similarly elicits antihypertensive effects in rat models of hypertension (Okamoto et al., 1991). Impairments in myocardial necrosis, ATP content, systolic and diastolic function are also attenuated in large animal models of cardiac I–R injury in vivo (Nakamura et al., 1982; Maulik et al., 2000). Attenuated oxidative stress accompanies coenzyme Q10 cardioprotection. These combined improvements in vascular and cardiac function observed with coenzyme Q10 may thus be the combined result of improved cellular bioenergetics, membrane-stabilizing properties and its powerful ROSsuppressing actions. As elevated oxidative stress is a major contributor to the pathogenesis of diabetes mellitus, a number of studies have also examined the efficacy of coenzyme Q10 in preventing the diabetes-induced vascular complications. It reduces systolic blood pressure and diastolic blood pressure in diabetic patients (Hodgson et al., 2002; Chew et al., 2008), with improvements in endothelium-dependent vasodilator tone (Watts et al., 2002). Despite the existence of the numerous studies discussed above, demonstrating the benefits of coenzyme

Q10 for treating cardiomyopathies, the impact of coenzyme Q10 on the cardiac structural and functional defects that characterize diabetic cardiomyopathy had largely not been considered. Recent preclinical evidence now suggests that the endogenous antioxidant coenzyme Q10 represents an effective antioxidant approach for specifically managing diabetic cardiomyopathy (Huynh et al., 2012, 2013). Chronic supplementation with coenzyme Q10 for 8–10 weeks, commencing several weeks after the documented onset of hyperglycemia, limits cardiomyocyte hypertrophy, cardiac fibrosis and several parameters of LV diastolic function, in both T1DM and T2DM mice. These protective actions are accompanied by significant attenuation of cardiac and systemic oxidative stress, LV NADPH oxidase activity and apoptosis, regardless of sex, concomitant obesity, or antihypertensive actions (Huynh et al., 2012, 2013). In addition to its antioxidant actions, coenzyme Q10 also limits LV expression of pro-inflammatory cytokines (Huynh et al., 2013), and preserves both LV activity of the cell survival kinase Akt, and LV expression of the Ca2+-handling protein, SERCA2a (Huynh et al., 2012). Taken together, this evidence warrants the prompt clinical investigation of coenzyme Q10 in patients affected by, or at high risk of, diabetes and its associated detrimental cardiac and vascular complications. 6.2. Exercise: a non-pharmacological therapy for diabetic cardiomyopathy Studies have shown that regular exercise is generally safe in HF patients and can improve cardiac function and quality of life (Giannuzzi et al., 2003; Pina et al., 2003; Wisloff et al., 2007). As such, exercise is now considered an integral component of the non-pharmacological management of patients with HF (Pina et al., 2003; Selig et al., 2010). Regular exercise of moderate intensity is also recommended as an important treatment and management strategy for patients with T2DM (Hordern et al., 2012), as regular exercise training has been shown to improve glycemic control, body composition, cardiovascular risk and general well-being in these patients (Snowling & Hopkins, 2006; Marwick et al., 2009; Chudyk & Petrella, 2011). A relatively recent study conducted in overweight-to-obese male patients with T2DM demonstrated that 12 weeks of progressive endurance/strength training was effective in improving insulin sensitivity and cardiac function in these patients (Schrauwen-Hinderling et al., 2011). The benefits of physical activity have been less clear in patients with T1DM, with many physicians in the past reluctant to prescribe exercise as it was considered of no benefit or to be associated with potential risks (e.g. hypoglycaemia). However, there are some studies to suggest exercise can be safe and beneficial in patients with T1DM. Adolescents with T1DM who participated in a 6-month exercise program had significantly lower HbA1c values, a reduced need for insulin, and improved waist circumference. This was associated with decreased cardiovascular risk factors, and the frequency of hypoglycaemic events (a risk associated with physical activity in diabetics) was not different between the controls and exercising groups (Salem et al., 2010). Finally, a recent large meta-analysis study concluded that exercise levels currently recommended by the major diabetes associations can be undertaken safely in T1DM with beneficial effects on cardiovascular disease and mortality, insulin resistance and well-being (Chimen et al., 2012). Though, further studies will be required to assess the most suitable form of exercise, intensity and duration. Collectively, clinical studies support the idea that regular physical activity improves well-being and reduces the risk of heart disease in patients with T1DM and T2DM. The positive effects of exercise on diabetes-associated cardiac dysfunction and cardiomyopathy have also been demonstrated in animal studies. Hearts of adult male STZ diabetic rats display evidence of cardiac dysfunction 8–9 weeks post-STZ, which is prevented in exercise trained rats (8–9 weeks of treadmill endurance training) (Paulson et al., 1987; Loganathan et al., 2007). In the biobreeding rat with autoimmune T1DM, treadmill running for 8 weeks protects against LV systolic and diastolic dysfunction (Loganathan

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et al., 2012). Diabetic rats (induced by high fat diet and low dose STZ) subjected to a 12-week exercise protocol (voluntary wheel running) were also protected against LV diastolic dysfunction (Epp et al., 2013). Animal studies have also investigated the possible mechanisms by which exercise provides cardiac protection in a setting of diabetes. Mechanisms associated with improved outcomes in exercise trained rodent models of diabetes include i) attenuation of collagen deposition (Searls et al., 2004; Loganathan et al., 2012), ii) the presence of more intact mitochondria (Searls et al., 2004), iii) attenuation of cardiac DAG (Loganathan et al., 2012), and iv) more favorable calcium homeostasis and/or expression of calcium regulating proteins including RyR2, SERCA2a, phospholamban and NCX1 (Shao et al., 2009; Stolen et al., 2009; Le Douairon Lahaye et al., 2012; Epp et al., 2013). 6.3. Cardiac phosphoinositide 3-kinase (p110α) signaling as a therapeutic target Utilizing cardiac-specific caPI3K transgenic mice, numerous studies have demonstrated that augmented PI3K(p110α) signaling preserves ventricular function, attenuates cardiac structural remodeling and prevents arrhythmogenic electrical remodeling in settings of cardiac pathology (McMullen et al., 2003; Pretorius et al., 2009; Lin et al., 2010). Increased PI3K(p110α) signaling also protects the diabetic heart against LV diastolic dysfunction, cardiomyocyte hypertrophy, myocardial fibrosis and apoptosis (Ritchie et al., 2012), as described in Section 3.5. In each of these studies, PI3K(p110α) signaling is increased in the heart prior to the cardiac insult, as the caPI3K transgene was driven using an α-myosin heavy chain promoter. In a clinical setting, it would be necessary to have an approach which allows PI3K(p110α) signaling to be increased after the disease has been established. In Section 6.6, we describe such a gene therapy approach which could be used to mimic the protective properties of the caPI3K transgene.

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6.6. Gene therapy for treatment of diabetic cardiomyopathy 6.6.1. Nerve growth factor (NGF) gene therapy As described in Section 1.2, diabetic patients can develop nerve damage to multiple organs including the heart (referred to as cardiac autonomic neuropathy). NGF has been implicated in protecting cardiomyocytes and promoting repair after a cardiac insult (Emanueli et al., 2002; Meloni et al., 2010). Ieda and colleagues demonstrate that cardiac-specific NGF transgenic mouse hearts are protected against sensory denervation in the STZ-induced diabetic model (Ieda et al., 2006). The same authors demonstrate that diabetes reduces cardiac NGF levels in rats, and that NGF gene delivery reduces cardiac neuropathy. NGF gene delivery using a hemagglutinating virus of Japan-liposome complex injected directly into the hearts of STZ diabetic rats after 8 weeks also rescues diabetic cardiac neuropathy (Ieda et al., 2006). More recently, NGF was delivered to the heart using adeno-associated viral (AAV) serotype 2 (AAV2, intramyocardial injection) or AAV9 (systemic delivery). AAV2 transduces a broad range of tissues, whereas AAV9 appears to transduce heart more effectively than other serotypes (Zincarelli et al., 2008). In mice with STZ T1DM, gene delivery of NGF (AAV2 and AAV9) preserves LV systolic and diastolic function, preserves microvessel density and cardiac perfusion, protects against cardiac fibrosis and apoptosis, and prevents the fall in pAkt-Foxo3 signaling (Meloni et al., 2012).

6.4. Protein kinase C signaling as a therapeutic target

6.6.2. Pro-viral integration site for Moloney murine leukemia virus-1 gene therapy Pim-1 is downstream of Akt and is important for cardiomyocyte contractile function and survival (Muraski et al., 2007, 2008). Katare and colleagues demonstrate that Pim-1 protein levels are depressed in STZ-diabetic mouse hearts (Katare et al., 2011). Systemic administration of AAV9-Pim-1 gene delivery for 16 weeks, commencing 4 weeks from the onset of diabetes, increases cardiac Pim-1 expression, in addition to improving LV diastolic function (E/A ratio), preserving SERCA2 gene expression, and preventing cardiac fibrosis, apoptosis, and development of HF (Katare et al., 2011).

Multiple PKC isozymes are reported to have a causal role in a diverse range of diseases. This has led to a number of PKC modulators entering clinical trials (Mochly-Rosen et al., 2012). As previously noted, PKCβ is activated in a setting of hyperglycemia and in the diabetic heart. Overall, results from clinical trials using drugs that target PKC have not been encouraging (Mochly-Rosen et al., 2012). However, clinical trials with the PKCβ inhibitor, ruboxistaurin, are considered potentially worthy of examination for diabetic cardiomyopathy. Ruboxistaurin appears to be well tolerated in diabetic patients (McGill et al., 2006; Geraldes & King, 2010; Aiello et al., 2011), and ruboxistaurin has beneficial effects on the heart in animal studies (Connelly et al., 2009; Ladage et al., 2011).

6.6.3. Phosphoinositide 3-kinase(p110α) gene therapy We recently demonstrated that gene delivery of caPI3K using AAV6 (which preferentially transduces cardiac and skeletal muscle) improves LV systolic function in mice with pre-existing cardiac dysfunction due to pressure overload-induced pathological LVH (Weeks et al., 2012). Improvement in heart function is associated with more favorable expression of SERCA2a, αMHC/βMHC ratio, pAkt and capillary density. Since we have also shown that transgenic caPI3K expression prevents the development of STZ-induced diabetic cardiomyopathy (see Section 3.5), it will be of interest to assess whether PI3K(p110α) gene therapy improves LV function in the diabetic heart.

6.5. Inhibition of the mitogen-activated protein kinase pathway

6.6.4. Translation of gene therapy into the clinic The translation of gene therapies into the clinic has not been without its challenges. However, improvements in vector design and manufacturing methods has provided new possibilities for this therapeutic approach (Wright, 2011). It is also noteworthy that the delivery of AAV vectors designed to treat the heart have proven to be safe in Phase I and II clinical trials, and results from an AAV1-based intervention in a phase 2 trial in patients with advanced HF are promising (Jaski et al., 2009; Jessup et al., 2011).

It remains unclear how effective inhibition of MAPK signaling in the diabetic heart is likely to be. Of the four major MAPK subfamilies, results from animal studies lend greatest support for therapeutic inhibition of p38 MAPK (see Section 3.4). Inhibition of p38 MAPK with a pharmacological inhibitor (SB 203580) in an STZ mouse model of diabetes has no significant impact on cardiac fibrosis or diastolic dysfunction but normalizes cytokine levels and improves systolic function (Westermann et al., 2006). Of note, most clinical trials using small molecule inhibitors of p38MAPK have been for inflammatory conditions (e.g. rheumatoid arthritis), and have been encumbered by issues including drug toxicity or systemic anti-inflammatory responses (Sweeney, 2009). The use of p38MAPK inhibitors in clinical studies for cardiovascular diseases have been fewer and were summarized in detail recently (Martin et al., 2012). In a setting of atherosclerosis there is evidence to suggest that dosing regimens which partially inhibit p38MAPK are effective in reducing inflammation (Martin et al., 2012).

6.7. Dysregulated microRNAs as a therapeutic target for diabetic cardiomyopathy As described in Section 2.6, a number of miRNAs are differentially regulated in LV biopsies of T2DM HF patients compared with nondiabetic HF patients (Greco et al., 2012). Thus, miRNA-based therapies may provide value in diabetic patients with cardiac pathology. The feasibility of therapeutics that inhibit miRNAs (known as antimiRs) in

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human disease has already been demonstrated, with an antimiR drug entering clinical trials (miravirsen, an inhibitor of miR-122, for treatment of hepatitis C virus, HCV). Treatment was well tolerated in HCV patients in the Phase 2a trial (Janssen et al., 2013). This has led to enthusiasm and anticipation for the development of further miRNA-based drugs. Pharmaceutical companies have invested significantly into miRNA-based therapies, and new companies specifically developing miRNA-based drugs for cardiovascular diseases have emerged (Dealwatch, 2011; van Rooij et al., 2012; Weber, 2013). 7. Summary Cardiovascular disease remains the primary cause of morbidity and mortality in the diabetic population. In addition to the increased risk of developing macrovascular diseases such as coronary artery disease, an increasing body of evidence indicate that diabetic patients are also susceptible to a specific cardiomyopathy characterized by early diastolic impairments, cardiac hypertrophy and increased myocardial fibrosis. Despite the numerous drugs targeted at improving glycemic control and restoring cardiovascular function currently available to diabetic patients, the incidence of cardiovascular disease continues to escalate. The development of newer drugs approved for use in these patients, including incretins and TZDs which have both anti-diabetogenic and cardioprotective properties, hold promise for the treatment of both the metabolic and cardiovascular afflictions associated with diabetes. An increased understanding of the cellular and molecular perturbations in diabetes, including increased oxidative stress and enhanced activation of protein signaling pathways, which contribute to the pathogenesis of diabetic cardiomyopathy, have supported the discovery of potential therapeutic strategies aimed at reduced diabetic cardiac disease. As oxidative stress is one of the major (and likely early) contributors to the development and progression of diabetes, strategies to reduce the production of ROS, or increase its degradation, such as with antioxidant supplementation, may be protective against diabetesinduced cardiac dysfunction and remodeling. Specific inhibitors or gene-targeted therapy aimed at either blunting protein signaling involved in pathological hypertrophy (e.g. PKCβ) or enhancing the expression of cardioprotective pathways (e.g. PI3K(p110α)) may represent novel strategies for the treatment of diabetic cardiomyopathy. Pre-clinical studies strongly suggest early ROS upregulation as a key precursor of diabetes-induced cardiac remodeling which in turn further exacerbates cardiac dysfunction in the progression towards HF. Analogous prospective studies in diabetic patients are lacking at present however, precluding clarification at which stage in the progression of diabetic cardiomyopathy therapies targeting ROS versus their downstream consequences might be appropriate. Further understanding of the mechanisms responsible for the onset of the functional and structural complications in the diabetic heart will undoubtedly aid the development of more precise therapeutics for the treatment of diabetic cardiomyopathy. Conflict of interest The authors declare that there are no conflicts of interest. Acknowledgments The authors thank Dr Nga Cao (Baker IDI) for the representative image of cardiac superoxide generation contained in Fig. 1. This work was supported by a National Health and Medical Research Council (NHMRC) of Australia project grant (ID526638 to RHR and JRM), and supported in part by the Victorian Government's Operational Infrastructure Support Program. KH was supported by an Australian Postgraduate Award. RHR and JRM are NHMRC Senior Research Fellows (IDs 472673, 586604). JRM is supported by an Australia Research Council Future Fellowship (FT0001657).

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