Oxidative Stress in Essential Hypertension and Role of Antioxidants

REVIEW ARTICLE

JIACM 2010; 11(4): 287-93

Oxidative Stress in Essential Hypertension and Role of Antioxidants M Beg*, A Gupta*, VN Khanna* Essential hypertension, or hypertension of unknown cause, accounts for more than 90% of cases of hypertension. It tends to cluster in families and represents a collection of genetically based diseases or syndromes with several resultant inherited biochemical abnormalities 1-4. The resulting phenotypes can be modulated by various environmental factors, thereby altering the severity of blood pressure elevation and the timing of hypertension onset. Many pathophysiologic factors have been implicated in the genesis of essential hypertension: increased sympathetic nervous system activity, perhaps related to heightened exposure or response to psychosocial stress; overproduction of sodium-retaining hormones and vasoconstrictors; longterm high sodium intake; inadequate dietary intake of potassium and calcium; increased or inappropriate renin secretion with resultant increased production of angiotensin II and aldosterone; deficiencies of vasodilators, such as prostacyclin, nitric oxide (NO), and the natriuretic peptides; alterations in expression of the kallikrein–kinin system that affects vascular tone and renal salt handling; abnormalities of resistance vessels, including selective lesions in the renal microvasculature; diabetes mellitus; insulin-resistance; obesity; increased activity of vascular growth factors; alterations in adrenergic receptors that influence heart rate, inotropic properties of the heart, and vascular tone; and altered cellular ion transport. The novel concept that structural and functional abnormalities in the vasculature, including endothelial dysfunction, increased oxidative stress, vascular remodelling, and decreased compliance, may antedate hypertension and contribute to its pathogenesis has gained support in recent years. A plethora of investigations provide strong evidence that oxidative stress is decisively involved in the pathogenesis of endothelial dysfunction, hypertension, and atherosclerosis. Several enzymes expressed in vascular tissue contribute to production and efficient degradation

of reactive oxygen species, and enhanced activity of oxidant enzymes and/or reduced activity of antioxidant enzymes may cause oxidative stress. Antioxidants may be more beneficial in primary prevention rather than in patients with advanced disease. However, there is evidence that some drugs that do not act as direct antioxidants, for example, statins and AT1 receptor antagonists, exert their therapeutic benefits – at least in part – through antioxidant actions. This may have several implications. First, testing diseased individuals for markers of oxidative stress could be used for risk stratification. Treatment with potent antioxidants may potentially be beneficial in this group of patients. Second, given the fact that dysregulated oxidant and antioxidant enzyme expression and function is found in patients with cardiovascular risk factors and specific pharmacological modulation of key enzymes, such as inhibition of the vascular NAD(P)H oxidase, may be an effective approach to reduce vascular oxidative stress and subsequent disease progression in humans that is potentially more powerful than the use of systemic antioxidants.

Oxidative stress and redox signalling in hypertension Metabolism of oxygen by cells generates potentially deleterious reactive oxygen species (ROS). Under normal conditions, the rate and magnitude of oxidant formation is balanced by the rate of oxidant elimination. However, an imbalance between prooxidants and antioxidants results in oxidative stress, which is the pathogenic outcome of oxidant overproduction that overwhelms the cellular antioxidant capacity. The kidney and vasculature are rich sources of NADPH oxidase – derived ROS, which under pathological conditions play an important role in renal dysfunction and vascular damage. Strong experimental evidence indicates that increased oxidative stress and associated oxidative damage are mediators of renovascular injury in cardiovascular pathologies.

* Professor, Department of Medicine, C-16, Zakir Bagh, A.M.U. Campus, A.M.U., Aligarh 202 002, Uttar Pradesh.

Increased production of superoxide anion and hydrogen peroxide, reduced nitric oxide synthesis, and decreased bioavailability of antioxidants have been demonstrated in experimental and human hypertension. These findings have evoked considerable interest because of the possibilities that therapies targeted against free radicals by decreasing ROS generation or by increasing nitric oxide availability and antioxidants may be useful in minimising vascular injury and renal dysfunction and thereby prevent or regress hypertensive end-organ damage. Compelling experimental evidence indicates that reactive oxygen species (ROS) play an important pathophysiological role in the development of hypertension. This is due, in large part, to O2– excess (oxidative stress) and decreased NO bioavailability in the vasculature and kidneys and to ROS-mediated cardiovascular remodelling5-7. In human hypertension, biomarkers of systemic oxidative stress are elevated8. Treatment with superoxide dismutase (SOD) mimetics or antioxidants improves vascular and renal function, regresses vascular remodelling, and reduces blood pressure (BP) 9,10. Mouse models deficient in ROSgenerating enzymes have lower BP compared with wildtype counterparts, and angiotensin II (ang II) infusion fails to induce hypertension in these mice11. Furthermore, experimental models with compromised antioxidant capacity develop hypertension12. In cultured vascular smooth muscle cells (VSMCs) and isolated arteries from hypertensive rats and humans, ROS production is enhanced, redox-dependent signalling is amplified, and antioxidant bioactivity is reduced13. Accordingly, evidence at multiple levels supports a role for oxidative stress in the pathogenesis of hypertension. ROS in other organ systems, such as the heart, nervous system, and kidneys, have also been implicated in the pathophysiology of hypertension. In particular, increased renal O2– production is associated with NO bioi-nactivation, which influences afferent arteriolar tone, tubulo-glomerular feedback responses, and sodium reabsorption, important in longterm BP regulation14. These aspects are examined in recent excellent reviews15,16.

ROS in vascular damage in hypertension Vascular ROS are produced in endothelial, adventitial, and

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VSMCs and derived primarily from NAD(P)H oxidase, a multi-subunit enzyme catalysing O2– production by the 1 electron reduction of oxygen using NAD(P)H as the electron donor: 2O 2 +NAD(P)H2O 2– +NAD(P)+H +17 . Vascular NAD(P)H oxidase is regulated by humoral (cytokines, growth factors, and vasoactive agents) and physical factors (stretch, pulsatile strain, and shear stress)18. Physiologically, ROS are produced in a controlled manner at low concentrations and function as signalling molecules19 to maintain vascular integrity by regulating endothelial function and vascular contraction-relaxation. Under pathological conditions, increased ROS bioactivity leads to endothelial dysfunction, increased contractility, VSMC growth, monocyte invasion, lipid peroxidation, inflammation, and increased deposition of extracellular matrix proteins, important factors in hypertensive vascular damage20,21. Impaired endothelium-mediated vasodilation in hypertension has been linked to decreased NO bioavailability. Vasomotor tone is also modulated through direct ROS effects on [Ca2+]22,23. Molecular processes underlying ROS-induced vascular changes involve activation of redox-sensitive signalling pathways. Superoxide anion and H2O2 stimulate mitogenactivated protein kinases, tyrosine kinases, and transcription factors (NFκB, AP-1, and HIF-1) and inactivate protein tyrosine phosphatases19,24. ROS also increase [Ca 2+ ]i and upregulate protooncogene and proinflammatory gene expression19. These processes occur through oxidative modification of proteins by altering important amino acid residues, by inducing protein dimerisation, and by interacting with metal complexes such as Fe-S moieties 19 . Changes in the intracellular redox state through thioredoxin and glutathione systems may also influence signalling events19,24.

Oxidative stress in experimental hypertension Vascular oxidative stress has been demonstrated in spontaneous (genetic) and experimental hypertension. Spontaneously hypertensive rats (SHR) and stroke-prone SHR, genetic models that develop hypertension spontaneously, exhibit increased NAD(P)H driven O2– generation in resistance (mesenteric) and conduit (aortic) vessels 25,26. This is associated with NAD(P)H oxidase

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subunit overexpression and enhanced oxidase activity25,27. Several polymorphisms in the promoter region of the p22phox gene have been identified in SHR28. This has clinical relevance because an association between a p22phox gene polymorphism and NAD(P)H oxidase-mediated O 2– production in the vascular wall of patients with hypertension and atherosclerosis has been described. Increased expression of p47phox has been reported in the renal vasculature, macula densa, and distal nephron from young SHR, suggesting that renal NAD(P)H oxidase upregulation precedes development of hypertension29. Treatment with antioxidant vitamins, NAD(P)H oxidase inhibitors, SOD mimetics, and BH4 and Ang II type-1 (AT1) receptor blockers decrease vascular O2– production and attenuate development of hypertension in these models25,26. Taken together, these findings suggest that oxidative stress in genetic hypertension involves enhanced NAD(P)H oxidase activity and dysfunctional endothelial nitric oxide synthase (uncoupled NOS) and is regulated, in part, by AT1 receptors. Vascular oxidative stress has also been demonstrated in experimentally-induced hypertension, such as Ang II– mediated hypertension, Dahl salt-sensitive hypertension, lead-induced hypertension, obesity-associated hypertension, mineralocorticoid hypertension, and aldosterone-provoked hypertension30-32. Activation of vascular NAD(P)H oxidase and xanthine oxidase and endothelial nitric oxide synthase uncoupling33,34 have been implicated in amplified O 2– generation in experimental hypertension. Inhibition of ROS generation with apocynin (NAD(P)H oxidase inhibitor) or allopurinol (xanthine oxidase inhibitor) and radical scavenging with antioxidants or SOD mimetics decrease BP and prevent development of hypertension in most hypertensive models25,26,29. These beneficial effects have been attributed to normalisation of endothelial function, regression of vascular remodeling, reduced vascular inflammation, and improved renal function.

Oxidative stress in human hypertension Clinical studies demonstrated increased ROS production in patients with essential hypertension, renovascular hypertension, malignant hypertension, and preeclampsia35. These findings are based, in general, on increased levels of plasma thiobarbituric acid-reactive Journal, Indian Academy of Clinical Medicine

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substances and 8-epi-isoprostanes, biomarkers of lipid peroxidation and oxidative stress36. Accumulation of ROS by-products from oxidised genomic and mitochondrial DNA have also been demonstrated in hypertensive individuals. Polymorphonuclear leukocytes and platelets, rich O2– sources, also participate in vascular oxidative stress and inflammation in hypertensive patients37. Decreased antioxidant activity (SOD, catalase) and reduced levels of ROS scavengers (vitamin E, glutathione) may contribute to oxidative stress36. Activation of the renin-angiotensin system has been proposed as a mediator of NAD(P)H oxidase activation and ROS production. In fact, some of the therapeutic BP-lowering actions of AT1 receptor blockers and angiotensin-converting enzyme (ACE) inhibitors have been attributed to NAD(P)H oxidase inhibition and decreased ROS production38.

Oxidative stress and inflammation in hypertension According to the traditional view, hypertension acts as a major determinant of endothelial dysfunction and vascular damage, promoting inflammatory activation of endothelial cells, recruitment of inflammatory cells in the arterial wall and activation of vascular resident elements. In agreement with this theory, it has been shown that an inflammatory response can develop in the arteries of animal models of hypertension. This phenomenon is characterised by the expression of cytokines (IL-6, IL-1, TNF-α), chemokines (MCP-1), adhesion molecules (ICAM1, VCAM-1), and has been linked to NF-B system activation39,40. Mechanisms leading to this inflammatory response are not clarified and can include both mechanical stress of the arterial wall and pro-inflammatory effects of humoural factors, such as angiotensin II (Ang II). Accumulating evidence from basic science researches and clinical studies showed that Ang II, besides regulating the vascular tone, may exert some pro-inflammatory effects on the arterial wall. Ang II, in fact, induces NF-B activation triggering the production of inflammatory cytokines, promotes the activation of NADPH oxidase followed by the release of reactive oxygen species (such as superoxide anion) and impairs endothelium-dependent vasodilatation by reducing nitric oxide (NO) generation. The treatment of animal models of hypertension with

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angiotensin II receptor blockers (ARBs) reverses most of the detrimental effects of Ang II on endothelial function and reduces the level of inflammatory activation in the vessels. These basic science results were recently confirmed by clinical studies showing that treatment with ARBs can reduce the circulating levels of some inflammatory mediators, such as IL-6, TNF-α, MCP-1, and CRP41,42. Mechanical stress and humoural factors are also considered important stimuli for the activation of cellular elements resident in the media or adventitia layers of the arterial wall. In this context, a major role is played by vascular smooth muscle cells (VSMCs) which display remarkable plasticity in terms of differentiation, proliferation, and motility. Studies observed that specific immature type of VSMC populations exist in the arterial wall, and they play a fundamental role in the progression of vascular remodelling in hypertension43. The VSMC could undergo a phenotypic dedifferentiation process leading to the acquisition of a ‘synthetic’ (or undifferentiated) phenotypic profile followed by migration towards the intima layer and the production of new collagen matrix. Endothelial dysfunction, inflammatory cells recruitment and the neointima formation are now considered initial steps for atherogenesis development and may help to define the pathophysiological connection between hypertension and atherosclerosis development. The amplification of the inflammatory response in the artery could increase the plasma levels of the circulating inflammatory molecules, and could partly explain the low-grade inflammatory status observed in hypertensive subjects.

Modulating ROS bioavailability Therapeutic role in human hypertension Based on experimental evidence of the importance of oxidative stress in vascular damage, there has been great interest in developing strategies that target ROS in the treatment of hypertension and other cardiovascular diseases. Therapeutic approaches that have been considered include mechanisms to increase antioxidant bioavailability or to reduce ROS generation by decreasing activity of O 2 – -generating enzymes. Gene therapy targeting oxidant systems are also being developed, but their use in clinical hypertension remains unclear.

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The potential of antioxidants in treating conditions associated with oxidative stress is supported by experimental investigations, observational findings, small clinical studies, and epidemiological data44,45. However, findings are inconsistent and clinical trial data are inconclusive. To date, at least 7 large trials have been published regarding antioxidant vitamin effects on risks of cardiovascular disease: the Cambridge Heart Antioxidant Study (CHAOS; 2002 patients); Alpha Tocopherol, Beta-Carotene cancer prevention study (ATBC; 27 271 males); Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto Miocardico (GISSI)-Prevenzione trial (3,658 patients); Heart Outcomes Prevention Evaluation (HOPE) study (2,545 subjects); Medical Research Council/British Heart Foundation (MRC/BHF) heart protection study (20,556 adults); Primary Prevention Project (PPP; 4,495 patients); and the Antioxidant Supplementation in Atherosclerosis Prevention (ASAP) study (520 subjects) have recently been reviewed46,47. Except for the ASAP study, which demonstrated that 6year supplementation of daily vitamin E and slow-release vitamin C reduced progression of carotid atherosclerosis, the other studies failed to demonstrate significant beneficial effects of antioxidants on BP or on cardiovascular end points. Overall, data from large prospective randomised clinical trials failed to demonstrate beneficial cardiovascular effects of antioxidants. Potential reasons relate to (1) antioxidants used, (2) patients included in trials, and (3) the trial design itself. With respect to antioxidants, it is possible that agents examined were ineffective and inappropriate and that dosing regimens and duration of therapy were insufficient. For example, vitamins C and E, the most widely examined antioxidants in trials, may have prooxidant properties, with harmful and deleterious interactions. It is also possible that orally administered antioxidants may be inaccessible to the source of free radicals, particularly if ROS are generated in intracellular compartment and organelles. Furthermore, antioxidant vitamins do not scavenge H2O2 or HOCl, which may be more important than O2– in hypertensive vascular damage. Regarding individuals included in large trials, most subjects had significant cardiovascular disease, in which case damaging effects of oxidative stress may be irreversible. Another confounding factor is that most of


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the enrolled subjects were taking aspirin prophylactically. Because aspirin has intrinsic antioxidant properties48, additional antioxidant therapies may be ineffective. Moreover, in patients studied in whom negative results were obtained, it was never proven that these individuals had increased oxidative stress. Finally, none of the large clinical trials were designed to examine effects of antioxidants specifically on BP.

Antioxidants in hypertension Although the cause is not known, essential hypertension may develop through a combination of genetic and lifestyle factors. Excesses in sugar and salt and/or deficiencies in antioxidant vitamins have been linked to hypertension 49. Two studies in 1997 and 2001 that investigated Dietary Approaches to Stop Hypertension (DASH) demonstrated that a diet rich in fruit, vegetables, and low-fat dairy products, that includes whole grains, modest portions of lean meat and nuts, and that is low in salt and sugar significantly reduced blood pressure in both hypertensive and normotensive people50,51. Fruits, nuts, vegetables, and whole grains are major sources of antioxidant vitamins including vitamin C and E52. Lean meats and low-fat dairy products may provide ample amounts of dietary protein containing the antioxidant amino acid cysteine. These nutrients may be important contributing factors to the antihypertensive effects of the DASH diet. Antioxidants occur naturally in the diet, may be taken as dietary supplements, and some are produced endogenously. They are necessary components of the body’s metabolic processes and are essential to quench ROS. They are also part of the electron transport chain of respiratory metabolism. Antioxidants work together to maintain adequate total antioxidant capacity by acting in the place of another or by regenerating each other55. Antioxidants of higher electronegativity will regenerate those of lower electronegativity. Current therapies for hypertension normalise blood pressure by various means without removing the cause. Many of these treatments are prone to side-effects which may result in poor compliance. The ideal treatment would be a natural compound which would address the cause of the disease and could control blood pressure without side-effects.


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Under normal conditions ROS/oxidative stress is maintained at a low level by cellular antioxidants and antioxidant enzymes. In addition to their unique metabolic functions, antioxidants work together to provide total antioxidant capacity to the body. In the case of a deficiency of one antioxidant, or in the face of increased oxidative stress, other antioxidants will work to maintain adequate antioxidant activity.This sparing action will allow specific antioxidants to carry-out their unique functions. For example, if oxidative stress increases, lipoic acid supplementation will increase total antioxidant capacity thus sparing vitamin C and allowing it to maintain its function in hydroxylation reactions. Antioxidants have also been shown to regenerate each other from their oxidised to reduced forms56-59. For example, vitamin E radical (oxidised) is regenerated to vitamin E (reduced) by vitamin C (ascorbate) or coenzyme Q10 (reduced). These antioxidants are, in turn, regenerated by dihydrolipoic acid.

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A N N O U N C E M E N T M.R.C.P. EXAMINATION in India Applications are invited from the prospective candidates for the following forthcoming Examinations:

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MRCPI Part I General Medicine MRCPI Part I Paediatrics MRCPI Part II Written General Medicine MRCPI Part II Clinical General Medicine

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56. Packer L, Tritschler HJ, Wessel K. Neuroprotection by metabolic antioxidant alpha-lipoic acid. Free Rad Biol Med 1997; 22: 359-78. 57. Frei B, Kirn MC, Ames BN. Ubiquinol-10 is an effective lipidsoluble antioxidant at physiological concentrations. Proc Natl Acad Sci USA 1990; 87: 4879-83.

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55. Wilson FH, Disse-Nicodème S, Choate KA et al. Human hypertension caused by mutations in WNK kinases. Science 2001; 293: 1107-12.


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