Pleiotropic antioxidant potential of rosuvastatin in preventing cardiovascular disorders

European Journal of Pharmacology 711 (2013) 57–62

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Pleiotropic antioxidant potential of rosuvastatin in preventing cardiovascular disorders Rajkiran Mahalwar, Deepa Khanna n Cardiovascular Pharmacology Division, Department of Pharmacology, Institute of Pharmacy, Rajendra Institute of Technology and Sciences (RITS), Sirsa 125055, India

art ic l e i nf o

a b s t r a c t

Article history: Received 11 February 2013 Received in revised form 12 April 2013 Accepted 18 April 2013 Available online 3 May 2013

Rosuvastatin is a promising synthetic hydrophillic statin which provides potential benefits in reducing cardiovascular risk factors. Rosuvastatin has potent ability to diminish low density lipoprotein, very low density lipoprotein, triglycerides and enhance high density lipoprotein level to manage high cholesterol level and associated cardiovascular diseases. Intriguingly, numerous studies demonstrated that rosuvastatin can reverse the cardiac disorders such as hypertension, atherosclerosis, ischemic heart disease, congestive heart failure and cardiomyopathy by reducing reactive oxygen species mediated oxidative stress. Rosuvastatin maintain the balance between oxidant generation and oxidant scavenging by reducing NADPH (nicotinamide adenine dinucleotide phosphate)-dependent production of reactive oxygen species, suppressing endothelial nitric oxide synthase (eNOS) uncoupling, inducing and upregulating antioxidant defense mechanism. This review, summaries pleiotropic antioxidant evidences of rosuvastatin in favor of cardioprotection. & 2013 Elsevier B.V. All rights reserved.

Keywords: Oxidative stress NADPH oxidase Rosuvastatin Antioxidant enzymes Cardiovascular disorder

Contents 1. 2.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 57 Role of oxidative stress . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 58 2.1. NADPH oxidase mediated oxidative stress . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 58 2.1.1. Rosuvastatin against NADPH oxidase derived oxidative stress . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 59 2.2. Uncoupled endothelial nitric oxide synthase mediated oxidative stress . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 59 2.2.1. Rosuvastatin against endothelial nitric oxide synthase uncoupling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 59 2.3. Reduced antioxidant enzymatic defense mediated oxidative stress . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 60 2.3.1. Rosuvastatin improve antioxidant defense . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 60 3. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 60 Acknowledgment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 60 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 60

1. Introduction Statins, 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors are effective in preventing the pathogenesis of cardiovascular disorders (Davignon, 2004; Kapur and Musunuru, 2008; Zhou and Liao, 2009; Balakumar and Mahadevan, 2012). Clinically, along with lipid dependant effects of statins, nonlipid-dependent effects are also

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0014-2999/$ - see front matter & 2013 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.ejphar.2013.04.025

beneficial in primary and secondary prevention of coronary heart diseases by restoring nitric oxide (NO) mediated-endothelial function, enhancing stabilization of atherosclerotic plaques, reducing oxidative stress and vascular inflammation (Takemoto and Liao, 2001; Liao and Laufs, 2005; Lahera et al., 2007). Statins inhibit oxidant formation by affecting NADPH oxidase, upregulating antioxidant enzymes and enhancing the bioavailability of NO which can neutralize radicals. Antioxidant effect of statins likely contribute to their clinical efficacy in managing cardiovascular diseases as well as other chronic conditions associated with increased oxidative stress (Stoll et al., 2004). Several studies proposed ‘Pleiotropic effects’ of

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statins as key properties to reduce cardiovascular morbidity and mortality (Lahera et al., 2007; Sadowitz et al., 2010). Rosuvastatin, a synthetic hydrophillic statin is widely used to treat dyslipidemia by lowering lipid density lipoprotein, triglycerides and increasing high density lipoprotein levels (Rosenson, 2003). Intriguingly, it has been demonstrated that reactive oxygen species generated oxidative stress and inflammation are potent target site for rosuvastatin in order to manage vascular dysfunction (Gómez-García et al., 2007). Reactive oxygen species is a result of imbalanced oxidant production and endogenous antioxidant defense mechanism which appreciate overproduction of reactive oxygen/nitrogen species and oxidative damage (Lobo et al., 2010). Rosuvastatin attenuate oxidative stress mediating several antioxidant effects viz, reduction of NADPH oxidase, suppression of endothelial nitric oxide synthase (eNOS) uncoupling, upregulation of antioxidant enzymatic defense mechanism and inhibition of hydrogen peroxide induced-DNA damage (Laufs et al., 2002; Grosser et al., 2004; Habibi et al., 2007; Schupp et al., 2008). This review will focus the attention of viewers on root cause of oxidative stress and numerous evidential proofs demonstrating the therapeutic benefits of rosuvastatin in ameliorating oxidative stress associated cardiovascular dysfunction.

retrenchment of reactive oxygen species resulting in deleterious oxidative stress (Fig. 1) (Dhalla et al., 2000; Sorescu and Griendling, 2002; Valko et al., 2007; Paravicini and Touyz, 2008; Zhang et al., 2012). NADPH oxidase is a multisubunit enzyme that catalyzes the reduction of molecular oxygen to form O2dˉ which is liable in pathogenesis of cardiomyocytes (Fig. 2) (Niesner et al., 2008; Arora et al., 2010). NADPH oxidase is readily available from endothelial cells, smooth muscle cells, infiltrated monocytes/ macrophages and fibroblasts (Sorescu et al., 2002; Zalba et al., 2007). Aberrant activation of NADPH oxidase in response to neurohormones (angiotensin II, tumor necrosis factor-α, norepinephrine) contributes to cardiac disorders (Fig. 1) (Sorescu and Griendling, 2002). Angiotensin II activates NADPH oxidase via angiotensin-1 receptors and increase NADPH derived-O2dˉ

2. Role of oxidative stress Oxidative stress plays peculiar role in myocardium and vascular deformities in different types of cardiovascular disease such as hypertension, atherosclerosis, ischemic heart disease, congestive heart failure and cardiomyopathy (Dhalla et al., 2000). In normal physiological conditions, rate and magnitude of oxidant formation is balanced with rate of oxidant elimination. Pathogenic outcome of oxidant over production and suppressed antioxidant defense causes disturbance in this equilibrium resulting in oxidative stress, which initiates subcellular changes leading to cardiomyopathy (Touyz, 2004; Venardos et al., 2007). Oxidative stress is due to the production of Reactive oxygen species, which involve free radicals and peroxides/non radical (Genestra, 2007; Paravicini and Touyz, 2008; Birben et al., 2012). Free radicals generation is exponentially involved in development of myocardial and vascular damage (Gey, 1993; Singal et al., 1998; Dhalla et al., 2000). Free radicals are species that contain one and more unpaired electrons (Paravicini and Touyz, 2008). Free radicals include hydroxyl, nitric oxide (NOd) radical, superoxide (O2dˉ), peroxyl, and lipid peroxyl. Some oxidants by themselves are not free radical but can easily generate free radicals. These oxidants marked as peroxides/nonradical are hydrogen peroxide, peroxynitrite, nitrous acid, dinitrogen trioxide, singlet oxygen, ozone, hypochlorous acid and lipid peroxide (Genestra, 2007; Lobo et al., 2010). Reactive oxygen species mediated oxidative stress is an initial cause of cardiovascular injury potentially deteriorating normal cellular function through lipid peroxidation, DNA strand breaking and proteins inactivation (Venardos et al., 2007; Paravicini and Touyz, 2008; Bagatini et al., 2011). Reactive oxygen species generate pressure overload left ventricle hypertrophy and contribute in pathophysiology of multiple diseases including atherosclerosis, hypertension, hypercholesterolemia, heart failure and diabetes (Li et al., 2002; Dikalov et al., 2007; Mazor et al., 2008; Zimmerman and Zucker, 2009). Diabetic patients are more susceptible to cardiovascular complications due to oxidative stress associated with free radical mediated lipid peroxidation (Likidlilid et al., 2010). 2.1. NADPH oxidase mediated oxidative stress In the cardiovascular system, expression of NADPH oxidase, uncoupled nitric oxide synthase, xanthine oxidase, peroxidase, lipoxygenases, cyclooxygenase enzymes, mitochondrial autooxidations and certain heme-containing proteins are obligated for

Fig. 1. Various biomarkers of oxidative stress causing cardiovascular disorders and their inhibition by rosuvastatin. Negative sign indicates inhibition; TNF indicates tumor necrosis factor; AT-II indicates angiotensin II; NADPH indicates nicotinamide adenine dinucleotide phosphate; SOD indicates superoxide dismutase; GSH indicates glutathione; ROS indicates reactive oxygen species; ox-LDL indicates oxidized low-density lipoprotein; LOX-1 indicates ox- LDL receptor; eNOS indicates endothelial nitric oxide synthase; NO indicates nitric oxide; DNA indicates deoxyribonucleic acid.

Fig. 2. Rosuvastatin against endothelial nitric oxide synthase uncoupling mechanism. Doted line indicates inhibition; eNOS indicates endothelial nitric oxide synthase; NO indicates nitric oxide; O2d− indicates superoxide; NOd indicates nitric oxide; ONOOˉ peroxynitrite indicates; BH4 indicates tetrahydrobiopterin; BH2 indicates 7, 8-Dihydrobiopterin; LOX-1 indicates ox- LDL receptor; TNF-α indicates tumor necrosis factor alpha; NADPH indicates nicotinamide adenine dinucleotide phosphate.

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production in vascular smooth muscle cells and fibroblasts (Bendall et al., 2002; Hanna et al., 2002; Adachi et al., 2004; Manrique et al., 2007; Zhang et al., 2007). 2.1.1. Rosuvastatin against NADPH oxidase derived oxidative stress Collections of studies have suggested that rosuvastatin attenuate oxidative stress by suppression of NADPH oxidase enzyme. Resch et al. (2006) demonstrated that clinical rosuvastatin therapy decrease oxidative stress biomarkers along with cholesterol reduction (Resch et al., 2006). Rosuvastatin impairs platelet aggregation by inhibiting NOX2 release, a specific marker of NADPH oxidase activation in hypercholesterolemic patients (Pignatelli et al., 2012). Rosuvastatin decrease cardiac oxidative stress by attenuating myocardial NADPH subunits (gp91(phox), p40(phox), p67(phox) and p22(phox)), and Rac1 resulting in lower production of radicals (Fig. 1) (Tian et al., 2007, Habibi et al., 2007; Schupp et al., 2008; Kang and Mehta, 2009). Rosuvastatin treatment decreased the p22phox subunit of NADPH in aortic wall before nitroglycerin exposure to rats. Further, nitroglycerin increased expression of gp91phox mRNA in two mice strains by in vivo exposure of was completely abolished by rosuvastatin (Otto et al., 2005; Otto et al., 2006). Rosuvastatin reduce the risk of developing hypertension and ocular diseases in rats by reducing NADPH oxidase activity (Sicard et al., 2005; Sicard et al., 2007). Tian et al. (2011) demonstrated that rosuvastatin produces vasoprotective effect in diabetic mice by inhibiting reactive oxygen species production mediated by the elevated expression of Angiotensin 1 receptor-NADPH oxidase (Tian et al., 2011). Rosuvastatin attenuated the Ang II-mediated upregulation of both p40 (phox) and gp91 (phox) subunits of NAPDH oxidase as well as NF-kappa in mice (Kang and Mehta, 2009). Rosuvastatin treatment decrease NADPH oxidasedependent superoxide production in Zucker obese rats (Erdos et al., 2006). Rosuvastatin prevents angiotensin II-induced vascular changes by decreasing NADPH oxidase-derived oxidant excess, restoring NO availability, reversal of COX-1 induction and its prostanoid production, and stimulation of endogenous vascular antioxidant defenses (Colucci et al. 2012). 2.2. Uncoupled endothelial nitric oxide synthase mediated oxidative stress Endothelial nitric oxide synthase (eNOS) maintain equilibrium of redox balance between reactive nitrogen species and reactive oxygen species insistent for the health of cardiac cells (Zhang et al., 2012). Nitric oxide synthase enzyme possesses the unique ability to get ‘Uncoupled’ and produce reactive oxygen species instead of NO, which contributes to increased oxidative stress in myocardium (Roe and Ren, 2012; Zhang et al., 2012). Oxidative stress suppresses NO synthesis by deactivation of eNOS (Liao et al., 1995; Wang et al., 1998; Blair et al., 1999). eNOS, a key enzyme regulate cardiovascular function by producing endothelium-derived relaxing factor/NO (Balakumar et al., 2012). Reactive oxygen species supress NO availability as a result of eNOS uncoupling and play an important role in cardiovascular disorders like hypertension, atherosclerosis, ischemic reperfusion injury, endothelial dysfunction, cardiomyopathy and diabetes mellitus (Faraci and Didion, 2004; Roe and Ren, 2012). Nitric oxide, a gaseous free radical is poorly reacting with most of the biomolecules (Halliwell et al., 1999). The beneficial scavenging action of NO against peroxyl radicals turns to be deleterious when NOd react with other free radicals especially O2dˉ (Fig. 2). Superoxide levels influence the reaction pathways open to nitric oxide by modulating the effect of NO and enzyme superoxide dismutase (SOD) (Pryor and Squadrito, 1995; Tousoulis et al., 2012). NADPH-oxidase derived O2dˉ avidly react with eNOS-

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derived NO to form peroxynitrite (Forstermann and Li, 2011; Tousoulis et al., 2012). Peroxynitrite is a potent and versatile nitrogen species that can attack a wide range of biological targets (Pryor and Squadrito, 1995). Peroxynitrite increase O2dˉ and decrease NO production by eNOS uncoupling and is able to oxidize the cofactor tetrahydrobiopterin, which is potent inhibitor of NOSdependent O2dˉ (Kuzkaya et al., 2003; Forstermann and Li, 2011). Deficiency of tetrahydrobiopterin produces eNOS uncoupling, which is associated with increased O2dˉ and decreased NO production (Fig. 2) (Kuzkaya et al., 2003; Li and Förstermann, 2009; Forstermann and Li, 2011). Peroxynitrite is protonated to form peroxynitrous acid, which can yield nitrogen dioxide and a hydroxyl radical (Pryor and Squadrito, 1995). In the vessel wall, peroxynitrite and peroxynitrous acid contribute to lipid peroxidation and membrane damage (O′Donnell and Freeman, 2001). TNF-α contributes in oxidative stress by increasing the concentration of O2dˉ along with peroxynitrite in the cytosol and hydrogen peroxide in mitochondria (Fig. 2) (Mariappan et al., 2012). Atherosclerosis is characterized by reduced large artery distensibility, paralleled by an increased peroxynitrite formation and nitration of tyrosine (3-NT) in proteins (Pirro et al., 2007). Oxidized low-density lipoprotein (ox-LDL) interacting with lectin-like ox-LDL receptors (LOX-1) are the major stimulus for cardiomyocytes growth (Pignatelli et al., 2012). Oxidized low-density lipoprotein-induce upregulation of LOX-1 and downregulation of eNOS.(Fig. 2) LOX-1 receptor play a critical role in atherosclerosis and endothelial dysfunction both of which are associated with diminished expression of constitutive eNOS (Morawietz, 2007).

2.2.1. Rosuvastatin against endothelial nitric oxide synthase uncoupling NO donor, L-arginine, folic acid, statins, angiotensin converting enzyme inhibitors, tetrehydrobiopterin and its precursor sepiapterin and NO synthase transcription enhancers maintain vascular homeostasis by upregulating and concomitantly maintaining eNOS activity thereby restoring NO (Li and Förstermann, 2009). Rosuvastatin restores eNOS, increase the production of NO, and decrease O2dˉ and 3-NT production. Further, it decreases expression of NADPH subunits (p47-phox, p67-phox, p22-phox), 8-hydroxy-2′-deoxyguanosine, caspase-3 and Bcl-2, which prevent oxidative stress and apoptosis induced in human umbilical vein endothelial cells by diabetes (Piconi et al., 2008). Aortic pulse wave velocity, a reliable measure of aortic stiffness and 3-NT, a marker of peroxynitrite-mediated oxidative stress in hypercholesterolemic patients are significantly reduced by short term rosuvastatin therapy (Pirro et al., 2007). Rosuvastatin increases vascular endothelial NO production and attenuates myocardial necrosis following ischemia and reperfusion in mice (Jone et al., 2002). Rosuvastatin improves endothelial function by inhibiting HMG-CoA reductase and increased systemic NO bioavailability in congestive heart failure rats. (Schäfer et al., 2005) Rosuvastatin dose-dependently upregulate eNOS expression and protect mice from cerebral ischemia (Laufs et al., 2002). Rosuvastatin improve nicotine-induced vascular endothelial abnormalities by activating eNOS and PPARγ signaling pathways. Further additional antioxidant and lipid lowering effects of rosuvastatin prevents vascular endothelial abnormalities (Kathuria et al., 2013). Rosuvastatin mediate anti-oxidant and antiinflammatory effects by reducing interleukin-6, TNF-α, triglycerides, total cholesterol, low density lipoprotein and increasing the high density lipoprotein levels (Gómez-García et al., 2007). Rosuvastatin attenuate expression of TNF-α and p38 MAPK showing favorable response on cardiac remodeling and cardiac function after acute myocardial infarction (Xu et al., 2010). Rosuvastatin attenuates angiotensin-II-mediated cardiomyocytes growth by

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inhibiting LOX-1 and angiotensin-1 receptor expression (Pignatelli et al., 2012). 2.3. Reduced antioxidant enzymatic defense mediated oxidative stress Venardos et al. (2007) demonstrated that the production of reactive oxygen species is controlled through endogenous free radical scavenger enzymes i.e. superoxide dismutase (SOD), glutathione peroxidase (GPX), catalase and thioredoxin reductase systems (Venardos et al., 2007). SOD decomposes O2dˉ anions into hydrogen peroxide and then enzyme catalase catalyze the decomposition of hydrogen peroxide into water and oxygen (Fig. 3). In vascular walls, SOD prevents the oxidation of biological molecules by limiting the increase concentration of O2dˉ radicals (Fang et al., 1998; Didion et al., 2002; Faraci and Didion, 2004). SOD1 (Cu-Zn-SOD), SOD2 (Mn-SOD) and SOD3 (extracellular (EC)–SOD) predominant isoforms of SOD are present within the cytosol and nucleus in the mitochondrial matrix (Faraci and Didion, 2004; Didion et al., 2002). Increased intracellular SOD1 protects the heart from ischemiareperfusion injury (Fukushima et al., 2006). Overexpression of SOD1 attenuates both apoptosis and the inflammatory response during ischemia-reperfusion injury by significantly reducing O2dˉ and TNF-α (Tanaka et al., 2004). In clinical research, the coronary artery diseases were found to be associated with decrease level of EC-SOD (Maksimenko and Vavaev, 2012). A variety of antioxidant enzymes involving superoxide dismutase, glutathione reductase, glutathione peroxidase and catalase are equipped in mammalian cell that represent the network of defenses against oxidative stress induced tissue damage (Fig. 3) (Blokhina et al., 2003; Zinkevich and Gutterman, 2011). Reactive oxygen species and reactive nitrogen species modify the functions of antioxidant enzymes, they downregulate superoxide dismutase and glutathione peroxidase which is associated with various oxidative conditions and concomitant cellular damage (Fujii and Taniguchi, 1999). Antioxidant defense protein heme oxygenase-1 attenuates the overall production of reactive oxygen species by generating carbon monoxide and potent antioxidant bilirubin (Yet et al., 2001; Lakkisto et al., 2002; Stocker and Perrella, 2006; Wang et al., 2010). Heme oxygenase-1 derived carbon monoxide produce anticipatory effect against hydrogen peroxide induced cardiomyocytes apoptosis and cell death (Lakkisto et al., 2002; Daiber et al., 2010). 2.3.1. Rosuvastatin improve antioxidant defense Rosuvastatin is able to restore the antioxidant defense by improving SOD1 expression thereby providing protection against oxidative stress, which is contributor to post ischemic injury in the

Fig. 3. Rosuvastatin restore antioxidant defense mechanism. Doted line indicates inhibition; O2− indicates superoxide; SOD indicates superoxide dismutase; H2O2 indicates hydrogen peroxide; GPX indicates glutathione peroxidase; GR indicates glutathione reductase; GSH indicates glutathione; GSSG indicates glutathione disulfide.

heart (Verreth et al., 2007). Rosuvastatin enhances the expression of glutathione synthase, glutathione peroxidase, glutathione reductase and glutamylcysteine synthetase, the rate limiting enzyme of glutathione synthesis. Rosuvastatin significantly increase the total glutathione content of glutathione-depleted HL-60 (human promyelocytic leukemia cells) (Schupp et al., 2008). Grosser et al. (2004) demonstrated that rosuvastatin when added exogenously to the cells, upregulate the antioxidant defense protein heme oxygenase-1 metabolite bilirubin, which virtually abolish NADPH-dependent oxidative stress (Grosser et al., 2004). DNA is the most important target of oxidative attack. The increased level of oxidative DNA damage potentially contributes in development of cardiovascular diseases (Ballinger et al., 2000). Rosuvastatin exert antioxidant effects through the induction of antioxidant enzymes, and by suppressing reactive oxygen species thus preventing DNA damage caused in human promyelocytic cell line HL-60 (Fig. 1) (Schupp et al., 2008).

3. Conclusion Updates on research tremendously aided in showing increased participation of reactive oxygen species and reduced antioxidant enzymatic defense in the pathogenesis of cardiovascular disorders. Rosuvastatin significantly reduces NADPH-dependent production of reactive oxygen species; suppress endothelial nitric oxide synthase (eNOS) uncoupling and upregulate antioxidant defense mechanism. In this review brief perspective on some of the current research carried out in the area for understanding role of reactive oxygen species and antioxidant defense enzymes and their management by rosuvastatin in cardiovascular dysfunctions is highlighted.

Acknowledgment We express our gratefulness to Dr. Pitchai Balakumar for their expertise suggestion and review, gratitude is extended to Dr. Rajendar Singh, Chairman, Shri Om Parkash, Director and Dr. Senthil Kumar, Principal of Rajendra Institute of Technology and Sciences, Sirsa, India, for their inspiration and constant support. References Adachi, T., Pimentel, D.R., Heibeck, T., Hou, X., Lee, Y.J., Jiang, B., Ido, Y., Cohen, R.A., 2004. S-glutathiolation of Ras mediates redox-sensitive signaling by angiotensin II in vascular smooth muscle cells. J. Biol. Chem. 279, 29857–29862. Arora, S., Vaishya, R., Dabla, P.K., Singh, B., 2010. NADPH oxidases in coronary artery disease. Adv. Clin. Chem. 50, 65–86. Bagatini, M.D., Martins, C.C., Battisti, V., Gasparetto, D., da Rosa, C.S., Spanevello, R.M., Ahmed, M., Schmatz, R., Schetinger, M.R., Morsch, V.M., 2011. Oxidative stress versus antioxidant defenses in patients with acute myocardial infarction. Heart Vessels 26, 55–63. Balakumar, P., Mahadevan, N., 2012. Interplay between statins and PPARs in improving cardiovascular outcomes: a double-edged sword? Br. J. Pharmacol 165, 373–379. Balakumar, P., Kathuria, S., Taneja, G., Kalra, S., Mahadevan, N., 2012. Is targeting eNOS a key mechanistic insight of cardiovascular defensive potentials of statins? J. Mol. Cell. Cardiol 52, 83–92. Ballinger, S.W., Patterson, C., Yan, C.N., Doan, R., Burow, D.L., Young, C.G., Yakes, F.M., Van Houten, B., Ballinger, C.A., Freeman, B.A., Runge, M.S., 2000. Hydrogen peroxide- and peroxynitrite-induced mitochondrial DNA damage and dysfunction in vascular endothelial and smooth muscle cells. Circ. Res. 86, 960–966. Bendall, J.K., Cave, A.C., Heymes, C., Gall, N., Shah, A.M., 2002. Pivotal role of a gp91 (phox)-containing NADPH oxidase in angiotensin II-induced cardiac hypertrophy in mice. Circulation 105, 293–296. Birben, E., Sahiner, U.M., Sackesen, C., Erzurum, S., Kalayci, O., 2012. Oxidative stress and antioxidant defense. World Allergy Organ J. 5, 09–19. Blair, A., Shaul, P.W., Yuhanna, I.S., Conrad, P.A., Smart, E.J., 1999. Oxidised low density lipoprotein displaces endothelial nitric-oxide synthase (eNOS) from plasmalemmal caveolae and impairs eNOS activation. J. Biol. Chem. 274, 32512–32519.

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