Fat intake and cardiovascular response - Springer Link

Fat Intake and Cardiovascular Response Marlen Damjanovi, MS, and Matthias Barton, MD

Corresponding author Matthias Barton, MD Klinik und Poliklinik für Innere Medizin, Departement für Innere Medizin, Universitätsspital Zürich, Rämistrasse 100, 8091 Zürich, Switzerland. E-mail: [email protected] Current Hypertension Reports 2008, 10:25–31 Current Medicine Group LLC ISSN 1522-6417 Copyright © 2008 by Current Medicine Group LLC

High dietary fat intake is a major risk factor for the development of obesity, which is frequently associated with diseases such as hypertension and diabetes and thus accelerated atherosclerosis. Angiotensin II and endothelin-1 are powerful growth factors and vasoconstrictors implicated in regulating vascular tone, vascular structure, and inflammation. Reduced bioactivity of nitric oxide and increased formation of reactive oxygen species (ROS) have been associated with obesity and high dietary fat intake. This article reviews the effects of high-fat diet on vascular functional changes in rodents and humans. Changes include alterations in vasoconstrictor function and receptor expression, and modulators of endothelium-dependent vascular tone (eg, nitric oxide- or endothelium-dependent contracting factor–mediated responses). Novel vasodilator effects of ROS and the anatomic heterogeneity of vascular responses are discussed. The beneficial effects of vasoactive mediators on vascular function could play a role for susceptibility to obesity-dependent hypertension, which is present in many, but not all, obese patients.

Introduction Obesity, one of the most important cardiovascular risk factors, has been implicated in the development of hypertension and atherosclerosis in developed countries, and its prevalence is increasing in developing countries [1–4]. Factors such as a diet rich in fat and sugars, lack of physical activity, genetic predisposition, age, hormonal influences, smoking, and stress facilitate the development of obesity [5]. Obesity-associated diseases (eg, hypertension and diabetes mellitus) are the major causes of stroke, myocardial infarction, disability, and renal disease [6]. This review article summarizes new insights in how fat intake is linked to changes in cardiovascular responses of vasoactive mediators and growth regulators. Definitions

of hypertension, links between obesity and hypertension, and effects of obesity on vascular reactivity are discussed along with the associated molecular changes. Information on vasoactive systems that play an important role in regulating vascular homeostasis (eg, the renin-angiotensin-aldosterone and endothelin [ET] systems and the L-arginine-nitric oxide [NO] pathway), and the formation of reactive oxygen species (ROS) are presented. Special attention is given to fat-induced effects on vasoreactivity.

Hypertension: A Major Risk Factor for Cardiovascular Disease In Western countries, arterial hypertension (systolic blood pressure values > 140/90 mm Hg) is a major health and economic problem [7,8]. Hypertension is one of the most important cardiovascular risk factors and frequently is associated with other risk factors such as obesity, insulin resistance, diabetes, high alcohol intake, high salt intake, and psychosocial stress [8,9]. Blood pressure is determined mainly by two factors: cardiac output and peripheral vascular resistance (BP = CO × PVR) [9]. Thus, changes in either cardiac output or peripheral vascular resistance will result in blood pressure changes. Defective renal sodium excretion and abnormal vasoconstriction have been identified as key factors for hypertension development [10]. Hypertension can be classified as primary or secondary [8,9]. Primary hypertension is a polygenic disease that is defined as an increase in blood pressure in the absence of any secondary medical cause [8]. In contrast, when a disease such as kidney disease causes high blood pressure, it is termed secondary hypertension [11]. In this context, obesity-associated hypertension can also be viewed as a secondary form of the disease. The adequate control and treatment of blood pressure remains a problem in primary medical care in Germany and Europe, where hypertension is greatly underdiagnosed [7,12]. This situation is important because the severity of hypertension is directly related to the increased risk for many cardio- and cerebrovascular diseases [8,9].

Obesity and Hypertension Obesity contributes to the development of associated diseases such as hypertension, insulin resistance, diabetes mellitus, and dyslipidemia, and thus to atherosclerosis [6,13]. Although the underlying mechanisms have been

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Pathogenesis of Hypertension: Genetic and Environmental Factors

only partly clarified, current experimental and clinical data indicate an important role for obesity in hypertension development [9]. Obesity-associated hypertension results in an increase of blood pressure partly by raising renal tubular reabsorption of sodium and impairing renal pressure natriuresis and via activation of the renin-angiotensin-aldosterone system (RAAS) and the sympathetic nervous system [14–16]. Studies in obese dogs and humans have demonstrated RAAS activation [17]. Treatment with angiotensin II (Ang II) receptor antagonists and angiotensin-converting enzyme (ACE) inhibitors in obese dogs and humans decreases renal tubular sodium reabsorption, indicating an important role of angiotensin and/or aldosterone in obesity-induced hypertension associated with sodium retention [18,19••]. Obesity stimulates the sympathetic nervous system in the kidney, thereby contributing to increased arterial blood pressure; accordingly, pharmacologic blockade of B- and C- adrenergic receptors reduces arterial blood pressure more efficiently in obese dogs compared with nonobese dogs [15,16]. Increased glomerular filtration rate and renal plasma flow can be observed in obesity’s early stages [14–16]. Also, several reports have linked insulin resistance to sodium retention in the kidney, which affects blood pressure in prediabetic patients [20,21]. Structural and functional changes of insulin receptors are associated with insulin resistance and thereby contribute to sodium retention in obesity-induced hypertension [22]. Experimental studies in rats demonstrate that high dietary salt intake modifies insulin receptor function [23]. Insulin resistance and diabetes are associated with abnormal and increased vasoconstrictor activity [24–26,27•,28,29]. Hypertension as a consequence of obesity also causes vascular hypertrophy, which has long-term deleterious effects on vascular structure [30]. Factors contributing to obesity-induced hypertension include the RAAS, the sympathetic nervous system, structural changes in the kidney, insulin resistance, and altered vascular function.

Effects of Obesity on Vascular Reactivity The RAAS and endothelin system Angiotensin-mediated vascular reactivity The RAAS is crucially involved in regulating blood pressure [31], and convincing evidence exists that obesity is associated with RAAS activation [6,32•]. Ang II, the key vasoconstrictor peptide of the RAAS, is responsible for maintaining blood pressure and water balance [31]. Biosynthesis of Ang II occurs via the conversion of angiotensinogen into the inactive form angiotensin I (Ang I) by the endopeptidase renin, which is then cleaved into the active vasoconstrictor Ang II by ACE [31]. Ang II binds to two receptor subtypes, AT1 and AT 2 [33], with the AT1 receptor being the predominant vasoconstrictor receptor [34,35]. Crowley et al. [19••] recently demonstrated a critical role for the renal AT1 receptor in systemic

Ang II–induced hypertension and its associated cardiac hypertrophy. In the obese Zucker rat (a model of insulin resistance with mild hypertension), sensitivity to Ang II– mediated vasoconstriction after bolus injection of Ang II is increased in the renal artery in obese animals compared with controls [36]. Another study in the same animal model demonstrated that AT1 receptor–mediated contractile responses are increased in endothelium-denuded but not in endothelium-intact aortic rings. These investigators also showed increased AT1 receptor and endothelial NO synthase gene expression in the aorta in the presence of intact endothelium [37]. We previously reported that short-term treatment of mice with a high-fat diet increases Ang II–mediated contractions and vascular protein expression of the AT1 receptor, depending on the dietary fat content (Fig. 1). These findings are compatible with an important role of Ang II and the AT1 receptor in hypertension development upon fat intake [33]. In mice exposed to prolonged intake of a high-fat diet, Ang II–mediated contractions in the aorta were enhanced even further (Fig. 1). This effect was abolished in mice concomitantly treated with darusentan, a selective ETA-receptor antagonist, indicating that endogenous ET-1 regulates obesity-induced activation of Ang II–mediated vasoconstriction [24]. In contrast to the aorta, no changes in the responses were observed in the carotid artery (Fig. 1), indicating that the duration of fat intake affects the degree of vasoconstriction, and that changes display distinct effects only in selected vascular beds [24]. ET-mediated vascular reactivity ET-1 is the predominant isoform of the ET peptide family [38]. ET-1 stimulated Ang II formation in vitro by increasing the conversion of Ang I to Ang II in vascular cells [39,40]. On the other hand, infusion of Ang II into rats increased ET-1 peptide content, which is regulated in an ETA receptor–dependent fashion [41]. Thus, an autocrine regulation exists between angiotensin and endothelin in the vasculature, similar to what has been demonstrated in cardiac fibroblasts [42]. ET-1 is produced by vascular and nonvascular cells and is activated by several different stimuli [43]. ET-1 is generated through conversion of preproET-1 into big ET-1 by the action of a furin-like enzyme. Big ET-1 can be cleaved into ET-1 by several different enzymes, including various isoforms of endothelin-converting enzymes (ECE) [43], chymases [43], non-ECE metalloprotease [43], and matrix metalloproteinase-2 [43]. ET-1 acts through two specific receptors, ETA and ETB [24,38,43]. The ETA receptor is expressed on vascular smooth muscle cells and cardiac myocytes [43]. ETA receptor activation by ET-1 results in vasoconstriction and cell proliferation [43]. In comparison, the ETB receptor is expressed in vascular endothelial cells and contributes to NO and prostacyclin release, leading to vasodilation and inhibition of cell growth [43]. Accordingly, ET-1 may play a role in several cardiovascular diseases, including obesity and hypertension [44–46].

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Fat Intake and Cardiovascular Response Damjanovi and Barton 27

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Figure 1. Angiotensin II (Ang II)–mediated contractions (A) and AT1 and endothelin (ET) A receptor protein expression (B) in aorta of C57BL/6J mice fed with a control (CTL), high-fat (HF), or very high-fat (VHF) diet for 15 weeks. Ang II–mediated contractions increased depending on dietary fat content (A). Analysis of immunoblots of AT1 receptor demonstrates increased expression after VHF diet compared with CTL or HF diet. ETA receptor protein expression was increased with HF and VHF diets (B). Responses to Ang II in aorta and carotid artery of C57BL/6J mice fed a CTL, HF, or HF diet plus darusentan (DAR) for 30 weeks (C). In the aorta, Ang II–induced contractions strongly increased after HF diet compared with control. Chronic darusentan treatment completely prevented the enhanced responses to Ang II (left). In the carotid artery, no effect was observed with any treatment (right). Vascular hydroxyl radical (•OH) formation is shown under basal conditions and the effect of ET-1 on •OH generation in aortic rings of control and obese animals in which the stimulatory effect was more or less abrogated (D). Data are mean plus or minus SEM. RFU—relative fluorescence units. (Adapted from Barton et al. [24], Mundy et al. [27•], and Mundy et al. [28] with permission of the American Heart Association, the European Society of Cardiology, and the American Physiological Society.)

As shown in Figure 2, obesity induced by high dietary fat intake increases ET-1–mediated contractions in the aorta in mice. Increased ETA receptor protein expression was seen after 15 weeks of treatment with a high-fat diet, compared with the control animals (Fig. 1). Therefore, upregulation of the ETA receptor and increases in ET-1–mediated contractility after increased dietary fat intake suggest that ET-1 could contribute to obesity-associated hypertension. Indeed, in obese and hypertensive patients, Cardillo et al. [47] demonstrated that increased body mass index is associated with augmented ETAdependent vasoconstrictor activity. Studies in mice given a high-fat diet reported increased renal but not pulmonary ACE activity. Treatment with the nonpeptide ETA receptor antagonist darusentan for 30 weeks markedly reduced renal but not pulmonary ACE activity [24], independent of ACE mRNA expression, body weight, or blood pressure [24]. Long-term treatment with another ETA-selective receptor antagonist reduced arterial blood pressure in rats fed a high-fat diet, again suggesting an

important role of the ETA receptor in regulating arterial blood pressure in obesity [48].

Effects on NO- and ROS-dependent function NO bioactivity NO is a short-lived vasodilating and growth-inhibitory molecule that is secreted by many vascular cells [49]. NO mediates endothelium-dependent relaxation in conduit arteries [50], inhibits platelet adhesion, and inhibits smooth muscle cell migration and proliferation [49,51•]. NO and citrulline are generated by catalyzation of NADPH and O2-dependent oxidation of L-arginine through the enzyme NO synthase (NOS) [49,51•]. The three NOS isoforms are eNOS, neuronal NOS (nNOS), and inflammatory NOS (iNOS) [49]. Upon activation of eNOS by the acetylcholine receptor, phospholipase C is activated, resulting in formation of inositol 1,4,5-triphosphate (IP3) and diacylglycerol (DAG) from phosphatidylinositol 4,5-biphosphate [49,51•]. IP3 increases intracellular Ca2+ and activates calmodulin, which then binds to eNOS, which generates NO [49]. NO


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Figure 2. Upper panels: Endothelium-dependent responses to acetylcholine in thoracic aorta (A), carotid artery (B), and femoral artery (C). Lower panels: Effects of endothelin-induced contractions in thoracic aorta (A); responses to reactive oxygen species (ROS) in carotid artery (B) and femoral artery (C). High-fat (HF) diet attenuated relaxant responses to acetylcholine at high concentrations compared with control (CTL) diet (A). No effects were observed with the different dietary treatments in the carotid artery (B), whereas very high-fat diet (VHF) enhanced acetylcholine-mediated relaxation in the femoral artery (C). In animals fed a HF diet, contractions to endothelin increased compared to CTL diet (A). In the carotid artery, no effects of diets were observed on ROS or hydroxyl radical (•OH)–induced contractions (B), whereas in the femoral artery, ROS/•OH contraction was reversed into relaxation in mice fed a HF or VHF diet compared with CTL (C). (Adapted from Traupe et al. [25] and Bhattacharya et al. [56].)

diffuses from endothelial cells to vascular smooth muscle cells, where it stimulates the activation of soluble guanylate cyclase, generating cyclic guanosine 3´,5´-monophosphate (cGMP) [49]. This causes a decrease of intracellular Ca2+ by activating protein kinase G (PKG), leading to vascular relaxation [49,52]. NO synthase can also be activated by phosphorylation of Akt [53,54]. Most recently, endothelium-dependent relaxation mediated by hydrogen peroxide (H 2O2)–mediated activation of cGMP-dependent protein kinase GIB (PKGIB) has also been demonstrated [55••]. All cardiovascular risk factors and most cardiovascular diseases (including hypertension) are associated with reduced NO bioactivity. We have studied the effects of

obesity on endothelium-dependent vascular reactivity in the aorta of mice fed a high-fat diet for 30 weeks [25]. Also studied were the effects of short-term treatments with diets of different fat content on carotid and femoral artery function of mice [56]. In obesity, endothelium-dependent relaxation in the aorta is counteracted by the release of prostanoid endothelium-dependent contracting factors at a high concentration of acetylcholine (Fig. 2), thus attenuating NO-dependent endothelium-mediated vasoreactivity [25]. In control mice, endothelium-dependent vasodilation in the femoral artery was lower than in the carotid artery (Fig. 2). Diet with very high-fat content had no effect on vasodilation in the carotid artery, but unexpectedly

Fat Intake and Cardiovascular Response Damjanovi and Barton 29

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enhanced relaxation responses to acetylcholine in the femoral artery (Fig. 2). These data suggest an anatomic heterogeneity of endothelium-dependent vasoreactivity in different vascular beds in obesity, as has already been reported for lean animals [57,58]. Endothelium-mediated vasodilation in conduit arteries (eg, the aorta and carotid artery) is mediated mainly by NO [59], whereas in the femoral artery and the mesenteric artery endothelium-dependent relaxation is mediated largely by an endothelium-derived hyperpolarization factor [60,61]. ROS: novel regulators of obesity-associated vascular dysfunction Vascular endothelial and vascular smooth muscle cells produce ROS, such as superoxide anion (O2-), H 2O2 , and hydroxyl radical (•OH) [62]. The formation of these oxidants is mainly catalyzed by NADPH oxidase, which consists of two membrane-associated components, p22phox and p91phox, and two cytosolic subunits, p47phox and

p67phox [62]. Moreover, an important aspect is the socalled uncoupling of eNOS, leading to the generation of O2- and NO, which react and result in the formation of peroxynitrite [51•]. This may also play an important role in the development of vascular dysfunction associated with obesity and other cardiovascular factors [51•]. Under normal conditions ROS are produced at low concentrations and function as signaling molecules regulating endothelial and vascular responsiveness [62,63]. Inhibition of H 2O2 by catalase decreases endothelium-dependent hyperpolarization in murine mesenteric arteries [64]. In contrast, under pathophysiologic conditions, increases of ROS result in functional vascular changes (eg, enhanced contractility, vascular smooth muscle cell growth, monocyte invasion, and inflammation) [62,63,65]. Figure 2 shows the effects of ROS on vascular tone in the carotid and femoral arteries of mice fed diets of different dietary fat content. The results indicated that ROS caused contraction in the carotid artery independent of diet, but caused relaxation in the femoral artery after high-fat feeding [56]. These data suggest ROS has a bifunctional role supporting either a vasoconstrictor or vasodilator function, depending on the vascular bed affected. Other investigators have reported a role of ROS as a regulator of obesity-associated vascular dysfunction and cellular injury [66,67]. Investigators have shown that ET-1, which modulates growth, and formation of ROS such as O2- and H 2O2 also regulates vascular •OH formation in mice (Fig. 1) [68,69]. This stimulating effect of ET-1 on vascular •OH formation was abrogated in obese animals [27•]. Results of recent studies show that activation of cGMP-dependent PKGIB by dimerization in response to H 2O2 is involved in endothelium-dependent hyperpolarization of aortic rings [55••]. These investigators also showed that insulin, which is increased in patients with insulin resistance and obesity, causes PKGIBmediated endothelium-dependent hyperpolarization and relaxation [55••].

Conclusions High dietary fat intake is associated with numerous changes in the cardiovascular system, which can be linked to the premature development of cardiovascular diseases. There is now compelling evidence that obesity causes distinct changes in vascular reactivity and contributes to the risk for developing hypertension. The RAAS, endothelin system, NO, and ROS are all involved in these functional changes. Given the deleterious effects of high dietary fat intake on vascular reactivity and its implications for obesity-related diseases, early measures are recommended to prevent obesity and its associated diseases, including hypertension [2,7,70,71].

Disclosures Original work of the authors is supported by the Swiss National Science Foundation and the University of Zurich.

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