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Pleiotropic effects of statins: A boulevard to cardioprotection
Arabian Journal of Chemistry (2011) xxx, xxx–xxx
King Saud University
Arabian Journal of Chemistry www.ksu.edu.sa www.sciencedirect.com
REVIEW ARTICLE
Pleiotropic effects of statins: A boulevard to cardioprotection Ankur Rohilla a, Seema Rohilla a, Ashok Kumar b, M.U. Khan b, Aakash Deep a b c
c,*
Department of Pharmaceutical Sciences, Shri Gopi Chand Group of Institutions, Baghpat 250609, Uttar Pradesh, India Onkar College of Pharmacy, Sunam 148026, Punjab, India Department of Pharmaceutical Sciences, Maharshi Dayanand University, Rohtak 124001, Haryana, India
Received 22 March 2011; accepted 21 June 2011
KEYWORDS Statins; Pleiotropic; Cardioprotective; Antioxidant
Abstract 3-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, referred to as ‘‘statins’’ have been extensively reported to possess lipid lowering effects by inhibiting the synthesis of cholesterol by liver and thereby increasing hepatic cholesterol uptake and reducing circulating lipid levels. Growing body of evidences have shown that apart from lipid lowering effects, statins possess various pleiotropic effects that include improvement in endothelial dysfunction, increased expression of endothelial nitric oxide synthase (eNOS), enhanced bioavailability of nitric oxide (NO), potent antioxidant potential and anti-inflammatory properties. In relation to cardiovascular pathologies, statins have been shown to inhibit atrial myocardial remodeling, prevent atrial fibrillation, conserve NO production in heart failure, reduce activity of small G-proteins in cardiac hypertrophy and protect the myocardium from lethal ischemia/reperfusion (I/R) injury. The mechanisms underlying the cardioprotective potential include phosphatidyl inositol (PI3)-kinase/Akt/eNOS pathway, subsequent activation of ATP sensitive potassium (KATP) channels by NO resulting in improved myocardial metabolism, release of endogenous adenosine by increasing the activity of adenosine forming enzyme ecto-5V-nucleotidase, inhibition of reactive oxygen species (ROS) production, decrease in oxidative stress and attenuation of apoptosis. The present review article demonstrates the pleiotropic effects of statins beyond their lipid lowering effects. Moreover, the underlying mechanisms involved in stain-induced cardioprotection have been delineated. ª 2011 King Saud University. Production and hosting by Elsevier B.V. All rights reserved.
* Corresponding author. Mobile: +91 9896096727. E-mail address: [email protected] (A. Deep). 1878-5352 ª 2011 King Saud University. Production and hosting by Elsevier B.V. All rights reserved. Peer review under responsibility of King Saud University. doi:10.1016/j.arabjc.2011.06.025
Production and hosting by Elsevier
Please cite this article in press as: Rohilla, A. et al., Pleiotropic effects of statins: A boulevard to cardioprotection. Arabian Journal of Chemistry (2011), doi:10.1016/j.arabjc.2011.06.025
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A. Rohilla et al.
Contents 1. 2. 3. 4. 5. 6.
Introduction . . . . . . . . . . . . . . . . Pravastatin and cardioprotection . Atorvastatin and cardioprotection. Simvastatin and cardioprotection . Rosuvastatin and cardioprotection Conclusion . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . .
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1. Introduction The 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors known as statins are potent inhibitors of cholesterol biosynthesis and exert beneficial effects in the primary and secondary prevention of coronary artery disease (Liao and Laufs, 2005). In addition, statins have been shown to exert extrahepatic, cholesterol independent effects in animal studies that have been referred to as pleiotropic effects that include direct effects on vascular tissue, heart, kidney, bone, and glucose metabolism that are apparently independent of their action on blood lipids (Palinski, 2001; Ferro, 2002; McFarlane et al., 2002; Laufs and Bohm, 2005). These include effects on the cardiovascular system, kidneys, bone, and glucose metabolism. A number of clinical trials have shown that statins significantly reduce cardiovascular morbidity and mortality. Potential mechanisms that may mediate beneficial cardiovascular action of statins include modulation of endothelial function (Mital et al., 2000; Alvarez de Sotomayor et al., 2000; Mehta et al., 2001), anti-inflammatory action (Egashira et al., 2000; Jialal et al., 2001), antioxidant properties (Wagner et al., 2000), plaque stabilization (Crisby et al., 2001), and effects on thrombosis (Rosenson and Tangney, 1998) and vasculogenesis (Vasa et al., 2001). Statin is the generic suffix used to classify the HMG-CoA reductase inhibitors worldwide. The prefix is specific and identifies the pharmaceutical company that manufactures and distributes the drug: for example, lovastatin, mevastatin, pravastatin, atorvastatin, simvastatin, and rosuvastatin. Daiichi Sankyo in the year 1973 discovered the world’s first statin named mevastatin. Although mevastatin is not used in medical therapy, it is often used as a starting compound to manufacture other statins such as pravastatin, an active ingredient also developed by Daiichi Sankyo. The cardioprotective potential of statins has been confirmed by a wide array of studies with respect to cardiovascular pathologies in which statins have been shown to inhibit atrial myocardial remodeling, prevent atrial fibrillation, conserve NO production in heart failure, reduce the activity of small G-proteins in cardiac hypertrophy, contribute to post-ischemic myocardial repair through mobilization of endothelial progenitor cells and protect the myocardium from lethal I/R injury (Dimmeler et al., 2001; Laufs et al., 2002; Trochu et al., 2003; Porter et al., 2004a,b; Kumagai et al., 2004). The mechanisms underlying these protective effects include improvement in vascular relaxation by increasing eNOS expression and thereby enhancing NO release, decreasing neutrophil infiltration by inhibiting ROS production and attenuate apoptosis (Di Napoli et al., 2001; Wolfrum et al., 2004). The accumulation of intracellular ROS upregulates the Akt pathway, which in turn enhances the
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accumulation of intracellular ROS and ultimately induces apoptotic cell death and secondary necrotic cell death (Kawabata et al., 2001; Wolfrum et al., 2003; Verma et al., 2004). Experimental data suggested that NO is an important component of myocardial I/R injury and can modulate ROS metabolism by reaction with free radicals such as superoxide in the formation of peroxinitrite. Statins have been noted to possess potent antioxidant effects through suppression of distinct oxidation pathways which include formation of myeloperoxidase-derived and NO-derived oxidants accounting for their anti inflammatory and antioxidant actions. Moreover, the statin-induced cardioprotection has been noted to involve extracellular regulated kinase (ERK1/2)/nuclear factor-kappa B (NF-jB) pathway along with PI3-kinase/Akt/eNOS pathway (Wolfrum et al., 2004; Verma et al., 2004). In addition, statins has been reported to induce a significant decrease in tumor necrotic factor-alpha (TNF-a), interleukin-6 (IL-6) and malondialdehyde (MDA) along with a significant increase of superoxide dismutase (SOD) activity that accounts for its cardioprotective and antioxidant actions (Takemoto et al., 2001; Bokoch and Diebold, 2002; Maack et al., 2003) (Fig. 1). Furthermore, clinical studies have also demonstrated the cardioprotective role of statins in patients undergoing cardiopulmonary bypass surgery by showing significant beneficial
Statins Pravastatin, Atorvastatin, Simvastatin, Rosuvastatin
eNOS
TNF-α
ROS
IL-6
Apoptosis
NF-κB
NO
Decreased oxidative stress Enhanced antioxidant enzymes
Cardioprotection Figure 1 Signaling pathways involved in statin-mediated cardioprotection. eNOS, endothelial nitric oxide synthase; ROS, reactive oxygen species; TNF-a, tumor necrotic factor alpha; NFjB, nuclear factor kappa B; IL-6, interleukin-6; NO, nitric oxide.
Please cite this article in press as: Rohilla, A. et al., Pleiotropic effects of statins: A boulevard to cardioprotection. Arabian Journal of Chemistry (2011), doi:10.1016/j.arabjc.2011.06.025
Pleiotropic effects of statins: A boulevard to cardioprotection
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effects by decreasing lipid peroxidation levels and improving cardioprotective markers (Mehra et al., 2002; Wainwright, 2005). The present review article reveals the pleiotropic effects of statins along with the underlying mechanisms involved in stain-induced cardioprotection.
ventricular hypertrophy by reducing the levels of oxidative stress markers and matrix metalloproteinase activity in rat heart (Ichihara et al., 2006; Abe et al., 2006). Moreover, numerous experimental studies have reported that administration of pravastatin has been shown to hinder radical oxygen species production by inhibiting protein kinase C-delta (PKC-d) activation (Ceolotto et al., 2006; Kassan et al., 2010). The cardioprotective and antioxidant effect of pravastatin was further confirmed by the fact that treatment with pravastatin showed prevention of impaired NO-dependent vasodilation and NADPH oxidase-mediated-ROS generation by blocking the down-regulation of Akt/eNOS pathways in rats (Ohkawara et al., 2010). Furthermore, administration of pravastatin showed cardioprotection in rats as assessed by better recovery of cardiac function (improvement in heart rate, left ventricular developed pressure, coronary flow and coronary resistance,) less release of biomarkers of cardiac injury (lactate dehydrogenase, creatine kinase-MB and endothelin1) and attenuation of ventricular arrhythmias (ventricular tachyarrhythmia and ventricular fibrillation) (Li et al., 2010). Chronic use of pravastatin after infarction resulted in enhanced connexin-43 quantity by attenuating mevalonatedependent ET-1 production through PKC-dependent pathway confirming its antiarrythmic effect in rats (Chen et al., 2010). Additionally, pravastatin has been reported to significantly reduce the cardiac AT-II levels and angiotensin converting enzyme 1 and 2 expressions normalizing the cardiac sympathetic hyper-responsiveness in rats confirming its potent cardioprotective effect (Herring et al., 2010).
2. Pravastatin and cardioprotection Pravastatin, a member of the drug class known as statins, chemically is (3R,5R)-3,5-dihydroxy-7-((1R,2S,6S,8R,8aR)-6hydroxy-2-methyl-8-{[(2S)-2-methylbutanoyl]oxy}-1,2,6,7,8,8ahexahydronaphthalen-1-yl)-heptanoic acid (Fig. 2). It has been noted that the pravastatin therapy improved the endotheliumdependent coronary vasomotion that contributed in the improvement of myocardial perfusion as well as regression of coronary atherosclerosis. Treatment with pravastatin prevented the reperfusion-induced ventricular tachycardia and ventricular fibrillation in rats that evidenced its beneficial role in decreasing cardiovascular mortality (Chen et al., 2003). Moreover, pravastatin treatment has been noted to prevent cardiovascular remodeling in the spontaneous diabetic rat model by increasing the expression of cardiac eNOS and inhibiting the over expressions of fibrogenic/proinflammatory cytokines (Yu et al., 2004). Pravastatin treatment prevented cardiomyocyte cell death following simulated hypoxia and reoxygenation by increasing NO release, decreasing myocyte endothelin-1 (ET-1) production and increasing Akt phosphorylation that demonstrated the novel protective role of pravastatin in human ventricular cardiomyocytes independent of endothelial cells types (Verma et al., 2004; Favaro et al., 2008). Statin therapy may restore ischemic hearts to full functional integrity during cardioplegic arrest through a direct effect on cardiomyocyte survival showing its potential in attenuating heart failure (Verma et al., 2004; Bezerra and Mandarim-de-Lacerda, 2005; Reddy et al., 2005). Moreover, pravastatin has been noted to exert antihypertropic effects by activation of KATP channels resulting in the amelioration of cardiomyocyte hypertrophy in rabbits (Lee et al., 2004). Pravastatin administration improved flow-mediated dilatation revealing its pleiotropic effects during the early phase of acute coronary syndrome. In addition, the circulating lipid peroxidation products in patients with unstable angina decreased significantly with pravastatin therapy (Cannon et al., 2004; Karatzis et al., 2005; Ky et al., 2008). The antioxidant effect of pravastatin was further confirmed by the fact that pravastatin in combination with pioglitazone modulated ANG II-mediated oxidative stress, inhibiting mitogen-activated protein kinase (MAPK) and NF-jB activation in mice (Chen and Mehta, 2006). Further, administration of pravastatin attenuated left
Figure 2
Chemical structure of pravastatin.
3. Atorvastatin and cardioprotection Atorvastatin, another member of the drug class known as statins, chemically is (3R,5R)-7-[2-(4-fluorophenyl)-3-phenyl-4(phenylcarbamoyl)-5-(propan-2-yl)-1H-pyrrol-1-yl]-3,5-dihydroxyheptanoic acid (Fig. 3). It has been noted that atorvastatin treatment produced endothelium-dependent vasodilation and improved endothelial dysfunction in rats by decreasing oxidative stress (Aviram et al., 1998; Perticone et al., 2000). Atorvastatin showed protective effect in heart which is mediated by an increase in eNOS expression and thereby increase in NO bioavailability (Birnbaum et al., 2003). Administration with atorvastatin significantly reduced thiobarbituric acid reactive oxygen substances (TBARS) levels and lipid peroxide concentrations as well as increased the reduced glutathione levels, the oxidative stress markers, which further evidenced its antioxidant action (Mahfouz and Kummerow, 2005; Ozacmak et al., 2007). It has been widely accepted that myocardial injury is associated with increased oxidative stress which involves
Figure 3
Chemical structure of atorvastatin.
Please cite this article in press as: Rohilla, A. et al., Pleiotropic effects of statins: A boulevard to cardioprotection. Arabian Journal of Chemistry (2011), doi:10.1016/j.arabjc.2011.06.025
4 NADPH oxidase. Atorvastatin treatment reduced vascular and cardiac free radical formation, normalized the expression of the NADPH oxidase and showed anti-oxidative properties along with enhancement of NO synthesis (Mahfouz and Kummerow, 2005; Bolayirli et al., 2007). Moreover, administration of isoproterenol produced severe myocardial damage and oxidative stress in rats. Atorvastatin treatment reduced myocardial infarction in rat hearts as assessed in terms of improvement in serum parameters, ATPase activities and reduction in oxidative stress. The lipid-independent anti-oxidative and anti-inflammatory effects of atorvastatin involve ERK1/2/NF-jB-pathway that is noted to afford cardioprotection (Riad et al., 2007). Moreover, the decrease in oxidative stress in subjects with metabolic syndrome was also noted with atorvastatin treatment (Singh et al., 2008). Atorvastatin has been reported to induce a significant decrease in TNF-a, IL-6 and MDA along with a significant increase of SOD activity that accounts for its cardioprotective and antioxidant action (Castro et al., 2008). High-fat diets significantly increased the C-reactive protein (CRP) levels and oxidative stress and compromised mitochondrial response to ischemia that was found to be reversed by atorvastatin treatment in a high-fat diet rat model which provide a superior control of cardiovascular risk markers in diabetic and hyperlipidemic subjects (Matafome et al., 2008). Moreover, atorvastatin has been noted to reduce systemic oxidative stress by direct inhibition of protein oxidation and oxidative DNA damage (Aydin et al., 2009). Additionally, atorvastatin treatment reduced electrophysiological alteration induced by I/R in isolated rat hearts as assessed in terms of prolonging the effective refractory period mediated by activation of NO pathway ultimately enhancing the myocardial electrophysiological stability (Xu et al., 2010a,b). Furthermore, recent studies have demonstrated that atorvastatin inhibited homocysteine-induced NADPH oxidase activation, ROS accumulation and apoptosis through p38MAPK dependent mechanisms that contribute to atorvastatin-mediated card protective effects (Bao et al., 2010). An interesting study confirmed the cardioprotective effect of atorvastatin as assessed by restoration of the infarct size-limiting and contractile dysfunction-reducing effect of ischemic postconditioning in rat hearts, the mechanism of which involved increased phosphorylation of Akt and eNOS (Ying et al., 2010). Clinically, treatment of atorvastatin inhibited oxidative stress by adiponectin-mediated NADPH oxidase down-regulation in hypercholesterolemic patients that further evidenced atorvastatin’s antioxidant effect. The cardioprotective potential of atorvastatin was further confirmed by the fact that atorvastatin treatment reversed hypertension-induced cardiac remodeling in rats by down-regulating PKD and myocyte enhancer factor which may serve as a novel therapeutic target for atorvastatin in treating hypertensive patients (Bacova et al., 2010; Geng et al., 2010). 4. Simvastatin and cardioprotection Simvastatin, third member of the statins class, chemically is (1S,3R,7S,8S,8aR)-8-{2-[(2R,4R)-4-hydroxy-6-oxooxan-2yl]ethyl}-3,7-dimethyl-1,2,3,7,8,8a-hexahydrona phthalen-1yl-2,2-dimethylbutanoate (Fig. 4). Simvastatin is a potent cardioprotective agent that inhibit leukocyte endothelial cell interactions and preserve cardiac contractile function and
A. Rohilla et al.
Figure 4
Chemical structure of simvastatin.
coronary perfusion after myocardial I/R and this effect is mediated by enhanced endothelial release of NO (Lefer et al., 1999; Di Napoli et al., 2001). The cardioprotective effect of simvastatin in a model of I/R in the Langendorff rat heart has been reported as assessed in terms of increased eNOS expression and thereby increased NO bioavailability (Di Napoli et al., 2001). The leukocytic and aortic productions of ROS along with protein and lipid oxidation products such as TBARS were prevented in an experimental model by simvastatin confirming its antioxidant effect (Delbosc et al., 2002). It ahs been reported that simvastatin improved the erythrocyte filterability in patients with familial hypercholesterolemia evidencing its potential cardioprotective role in clinical patients (Koter et al., 2003). In addition, experimental studies have shown that administration of simvastatin attenuated the oxidative stress and afforded cardioprotection by decreasing MDA levels and increasing the SOD and NO levels (Bayorh et al., 2005; Yin et al., 2007). Further, treatment with simvastatin was noted to be effective in reducing the oxidative stress and infarction volume that was responsible for ameliorating ischemic damage in rats. It ahs been reported that simvastatin pretreatment significantly reduced reperfusion arrhythmias occurring after regional ischemia in an open chest diabetic-hypercholesterolemic rat model (Adameova´ et al., 2006). Simvastatin reduced the activity of NADPH-CoQ reductase, an enzyme required in generation of free radicals that further evidenced its potent role as an antioxidant (Kettawan et al., 2007). Clinical studies have also suggested the cardioprotective role of simvastatin in patients undergoing cardiopulmonary bypass surgery by showing significant beneficial effects by decreasing lipid peroxidation (Coccia et al., 2007). Moreover, the treatment with simvastatin has been noted to possess antioxidant effect in diabetic-hypercholesterolemic rats (Kuzelova´ et al., 2008). Furthermore, simvastatin treatment significantly improved endothelial function and reduced oxidative stress that evidenced its antioxidant action in order to afford cardioprotection (Tong et al., 2009). Decrease in postischemic recovery of left ventricular developed pressure, increase in ventricular fibrillation, lengthening the duration of ventricular tachycardia and increase in myocardial infarct size are the markers of myocardial damage that was found to be reversed by simvastatin treatment that confirmed its pleiotropic in both healthy and diseased individuals (Adameova et al., 2009). Additionally, simvastatin has been recently reported to significantly reduce total cholesterol, triglycerides, low density lipoproteins, conjugated diene, total peroxide, and malondialdehyde levels that further evidenced its potential role as antioxidant and cardioprotective agent (Kumar, 2010).
Please cite this article in press as: Rohilla, A. et al., Pleiotropic effects of statins: A boulevard to cardioprotection. Arabian Journal of Chemistry (2011), doi:10.1016/j.arabjc.2011.06.025
Pleiotropic effects of statins: A boulevard to cardioprotection
Figure 5
Chemical structure of rosuvastatin.
5. Rosuvastatin and cardioprotection Rosuvastatin, the latest member of statins class, chemically is (3R,5S,6E)-7-[4-(4-fluorophenyl)-2-(N002Dmethylmethanesulfonamido)-6-(propan-2-yl)pyrimidin-5-yl]-3,5-dihydroxyhept-6enoic acid (Fig. 5). It has been reported that treatment with rosuvastatin increased vascular endothelial NO production and attenuated myocardial necrosis following I/R in mice evidencing its potential cardioprotective effect (Jones et al., 2002). Moreover, rosuvastatin given 18 h before I/R has significantly improved left ventricular developed pressure and the maximal rate of development of left ventricular developed pressure in a rat model of I/R which provide evidence that rosuvastatin significantly attenuated cardiac contractile dysfunction in isolated perfused rat hearts (Ikeda et al., 2003). Administration with rosuvastatin has been noted to reduce arterial pressure in genetic hypertension and improve systemic and regional hemodynamics in hypertensive rat hearts confirming its potent cardioprotective role (Susic et al., 2003; Neto-Ferreira et al., 2011). In addition, it has been demonstrated that rosuvastatin exerted potent antioxidative effects which were capable of preventing DNA damage in vivo by involving the induction of the expression of antioxidant defense enzymes (Grosser et al., 2004; Schupp et al., 2008). Further, chronic treatment with rosuvastatin before ischemia reduced I/R injury in rat hearts and prevented coronary endothelial cell and cardiomyocyte damage by NO-dependent mechanisms (Di Napoli et al., 2005). Rosuvastatin significantly reduced infarct size in mice hearts after 60 min of I/R suggesting its potential as a cardioprotective agent as assessed by reduction in neutrophil infiltration and increasing the expression of eNOS and thereby increasing NO production (Weinberg et al., 2005). Additionally, rosuvastatin treatment has been reported to normalize the endothelial function and reduce the platelet activation in diabetic rats which may contribute to the reduction of cardiovascular events by statins in diabetic patients (Scha¨fer et al., 2007). The normalization of ROS production and platelet aggregation in a hamster model by rosuvastatin treatment has further confirmed its potential as a vasculoprotective and cardioprotective agent (Miersch et al., 2007; Almeid et al., 2009). The elevations of left ventricular wet weight, myocardial extracellular matrix content, diastolic stiffness, and alterations in systolic and diastolic function are the markers of heart failure that were noted to be inhibited by chronic rosuvastatin treatment in rat hearts (Loch et al., 2009). Furthermore, rosuvastatin treatment showed a protective role in rat model of left ventricular hypertrophy as assessed in terms of attenuation of myocardial fibrosis and left ventricular stiffness (Chang et al., 2009). Rosuvastatin treatment was noted to reduce plasma concentrations of total cholesterol, low density lipoproteins
5 and triglycerides, urine and plasma oxidative stress markers and plasma CRP in hypercholesterolemic patients that further evidenced its antioxidant effect (Yoshino et al., 2009; Koksal et al., 2010). It has been recently reported that rosuvastatin in combination with standard heart failure therapy results in a significant additional improvement in heart failure and cardiac remodeling in rats confirming its potent cardioprotective effect (Go´mez-Garre et al., 2010; Ying et al., 2010). In addition, short-term treatment with rosuvastatin significantly increased the number of circulating endothelial progenitor cells in patients with heart failure that further confirmed its antioxidant and cardioprotective effect providing further insights into its role in these individuals (Tousoulis et al., 2011). 6. Conclusion Accumulating evidence indicates that statin therapy favorably influences a number of diverse clinical events through both effects related to lowering of cholesterol levels and effects independent of the lowering of cholesterol levels. The latter effects are referred to as pleiotropic. The pleiotropic effects of the statins improve vascular relaxation, promote new vessel formation, inhibit platelet aggregation and reducing vascular inflammation. It is noteworthy that the pleiotropic properties of the statins have been beneficial in a variety of diseases that involve a number of organs and organ systems. By enhancing eNOS expression and thereby increasing NO bioavailability, reducing oxidative stress and proinflammatory cytokine production and preventing ROS production and apoptosis, the HMG-CoA reductase inhibitors may prove to be useful agents in treating patients with cardiovascular diseases. The findings of this study, therefore, may have important clinical implications since cardiovascular diseases are a major cause of morbidity and mortality worldwide. Moreover, the observations that acute exposure to statins may also afford cardioprotection imply their potential use in situations of controlled, deliberate myocardial I/R, such as coronary angioplasty, coronary artery by-pass grafting and cardiac transplantation that would open new doors for the treatment strategies of such patients. The beneficial role of statins in the experimental setting of myocardial I/R injury would surely open new gates in the treatment of patients presented with coronary heart disease. The clinical relevance of these effects is beginning to be recognized and further studies would be able to answer such questions in the near future. References Abe, Y., Izumi, T., Urabe, A., Nagai, M., Taniguchi, I., Ikewaki, K., Mochizuki, S., 2006. Cardiovasc. Drug Ther. 20, 273–280. Adameova´, A., Kuzelova´, M., Faberova´, V., Svec, P., 2006. Pharmazie 61, 807–808. Adameova, A., Harcarova, A., Matejikova, J., Pancza, D., Kuzelova, M., Carnicka, C., Svec, P., Bartekova, M., Styk, J., Ravingerova´, T., 2009. Physiol. Res. 58, 449–454. Almeid, E.A., Hernandes, D.B., Ozaki, M.R., Ramı´ rez-Nu´n˜ez, W.R., 2009. Arteriosclerosis 21, 263–267. Alvarez de Sotomayor, M., Herrera, M.D., Marhuenda, E., Andriantsitohaina, R., 2000. Br. J. Pharmacol. 131, 1179–1187. Aviram, M., Rosenblat, M., Bisgaier, C.L., Newton, R.S., 1998. Atherosclerosis 138, 271–280. Aydin, S., Uzun, H., Sozer, V., Altug, T., 2009. Pharmacol. Res. 59, 242–247.
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King Saud University
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REVIEW ARTICLE
Pleiotropic effects of statins: A boulevard to cardioprotection Ankur Rohilla a, Seema Rohilla a, Ashok Kumar b, M.U. Khan b, Aakash Deep a b c
c,*
Department of Pharmaceutical Sciences, Shri Gopi Chand Group of Institutions, Baghpat 250609, Uttar Pradesh, India Onkar College of Pharmacy, Sunam 148026, Punjab, India Department of Pharmaceutical Sciences, Maharshi Dayanand University, Rohtak 124001, Haryana, India
Received 22 March 2011; accepted 21 June 2011
KEYWORDS Statins; Pleiotropic; Cardioprotective; Antioxidant
Abstract 3-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, referred to as ‘‘statins’’ have been extensively reported to possess lipid lowering effects by inhibiting the synthesis of cholesterol by liver and thereby increasing hepatic cholesterol uptake and reducing circulating lipid levels. Growing body of evidences have shown that apart from lipid lowering effects, statins possess various pleiotropic effects that include improvement in endothelial dysfunction, increased expression of endothelial nitric oxide synthase (eNOS), enhanced bioavailability of nitric oxide (NO), potent antioxidant potential and anti-inflammatory properties. In relation to cardiovascular pathologies, statins have been shown to inhibit atrial myocardial remodeling, prevent atrial fibrillation, conserve NO production in heart failure, reduce activity of small G-proteins in cardiac hypertrophy and protect the myocardium from lethal ischemia/reperfusion (I/R) injury. The mechanisms underlying the cardioprotective potential include phosphatidyl inositol (PI3)-kinase/Akt/eNOS pathway, subsequent activation of ATP sensitive potassium (KATP) channels by NO resulting in improved myocardial metabolism, release of endogenous adenosine by increasing the activity of adenosine forming enzyme ecto-5V-nucleotidase, inhibition of reactive oxygen species (ROS) production, decrease in oxidative stress and attenuation of apoptosis. The present review article demonstrates the pleiotropic effects of statins beyond their lipid lowering effects. Moreover, the underlying mechanisms involved in stain-induced cardioprotection have been delineated. ª 2011 King Saud University. Production and hosting by Elsevier B.V. All rights reserved.
* Corresponding author. Mobile: +91 9896096727. E-mail address: [email protected] (A. Deep). 1878-5352 ª 2011 King Saud University. Production and hosting by Elsevier B.V. All rights reserved. Peer review under responsibility of King Saud University. doi:10.1016/j.arabjc.2011.06.025
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Please cite this article in press as: Rohilla, A. et al., Pleiotropic effects of statins: A boulevard to cardioprotection. Arabian Journal of Chemistry (2011), doi:10.1016/j.arabjc.2011.06.025
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A. Rohilla et al.
Contents 1. 2. 3. 4. 5. 6.
Introduction . . . . . . . . . . . . . . . . Pravastatin and cardioprotection . Atorvastatin and cardioprotection. Simvastatin and cardioprotection . Rosuvastatin and cardioprotection Conclusion . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . .
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1. Introduction The 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors known as statins are potent inhibitors of cholesterol biosynthesis and exert beneficial effects in the primary and secondary prevention of coronary artery disease (Liao and Laufs, 2005). In addition, statins have been shown to exert extrahepatic, cholesterol independent effects in animal studies that have been referred to as pleiotropic effects that include direct effects on vascular tissue, heart, kidney, bone, and glucose metabolism that are apparently independent of their action on blood lipids (Palinski, 2001; Ferro, 2002; McFarlane et al., 2002; Laufs and Bohm, 2005). These include effects on the cardiovascular system, kidneys, bone, and glucose metabolism. A number of clinical trials have shown that statins significantly reduce cardiovascular morbidity and mortality. Potential mechanisms that may mediate beneficial cardiovascular action of statins include modulation of endothelial function (Mital et al., 2000; Alvarez de Sotomayor et al., 2000; Mehta et al., 2001), anti-inflammatory action (Egashira et al., 2000; Jialal et al., 2001), antioxidant properties (Wagner et al., 2000), plaque stabilization (Crisby et al., 2001), and effects on thrombosis (Rosenson and Tangney, 1998) and vasculogenesis (Vasa et al., 2001). Statin is the generic suffix used to classify the HMG-CoA reductase inhibitors worldwide. The prefix is specific and identifies the pharmaceutical company that manufactures and distributes the drug: for example, lovastatin, mevastatin, pravastatin, atorvastatin, simvastatin, and rosuvastatin. Daiichi Sankyo in the year 1973 discovered the world’s first statin named mevastatin. Although mevastatin is not used in medical therapy, it is often used as a starting compound to manufacture other statins such as pravastatin, an active ingredient also developed by Daiichi Sankyo. The cardioprotective potential of statins has been confirmed by a wide array of studies with respect to cardiovascular pathologies in which statins have been shown to inhibit atrial myocardial remodeling, prevent atrial fibrillation, conserve NO production in heart failure, reduce the activity of small G-proteins in cardiac hypertrophy, contribute to post-ischemic myocardial repair through mobilization of endothelial progenitor cells and protect the myocardium from lethal I/R injury (Dimmeler et al., 2001; Laufs et al., 2002; Trochu et al., 2003; Porter et al., 2004a,b; Kumagai et al., 2004). The mechanisms underlying these protective effects include improvement in vascular relaxation by increasing eNOS expression and thereby enhancing NO release, decreasing neutrophil infiltration by inhibiting ROS production and attenuate apoptosis (Di Napoli et al., 2001; Wolfrum et al., 2004). The accumulation of intracellular ROS upregulates the Akt pathway, which in turn enhances the
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accumulation of intracellular ROS and ultimately induces apoptotic cell death and secondary necrotic cell death (Kawabata et al., 2001; Wolfrum et al., 2003; Verma et al., 2004). Experimental data suggested that NO is an important component of myocardial I/R injury and can modulate ROS metabolism by reaction with free radicals such as superoxide in the formation of peroxinitrite. Statins have been noted to possess potent antioxidant effects through suppression of distinct oxidation pathways which include formation of myeloperoxidase-derived and NO-derived oxidants accounting for their anti inflammatory and antioxidant actions. Moreover, the statin-induced cardioprotection has been noted to involve extracellular regulated kinase (ERK1/2)/nuclear factor-kappa B (NF-jB) pathway along with PI3-kinase/Akt/eNOS pathway (Wolfrum et al., 2004; Verma et al., 2004). In addition, statins has been reported to induce a significant decrease in tumor necrotic factor-alpha (TNF-a), interleukin-6 (IL-6) and malondialdehyde (MDA) along with a significant increase of superoxide dismutase (SOD) activity that accounts for its cardioprotective and antioxidant actions (Takemoto et al., 2001; Bokoch and Diebold, 2002; Maack et al., 2003) (Fig. 1). Furthermore, clinical studies have also demonstrated the cardioprotective role of statins in patients undergoing cardiopulmonary bypass surgery by showing significant beneficial
Statins Pravastatin, Atorvastatin, Simvastatin, Rosuvastatin
eNOS
TNF-α
ROS
IL-6
Apoptosis
NF-κB
NO
Decreased oxidative stress Enhanced antioxidant enzymes
Cardioprotection Figure 1 Signaling pathways involved in statin-mediated cardioprotection. eNOS, endothelial nitric oxide synthase; ROS, reactive oxygen species; TNF-a, tumor necrotic factor alpha; NFjB, nuclear factor kappa B; IL-6, interleukin-6; NO, nitric oxide.
Please cite this article in press as: Rohilla, A. et al., Pleiotropic effects of statins: A boulevard to cardioprotection. Arabian Journal of Chemistry (2011), doi:10.1016/j.arabjc.2011.06.025
Pleiotropic effects of statins: A boulevard to cardioprotection
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effects by decreasing lipid peroxidation levels and improving cardioprotective markers (Mehra et al., 2002; Wainwright, 2005). The present review article reveals the pleiotropic effects of statins along with the underlying mechanisms involved in stain-induced cardioprotection.
ventricular hypertrophy by reducing the levels of oxidative stress markers and matrix metalloproteinase activity in rat heart (Ichihara et al., 2006; Abe et al., 2006). Moreover, numerous experimental studies have reported that administration of pravastatin has been shown to hinder radical oxygen species production by inhibiting protein kinase C-delta (PKC-d) activation (Ceolotto et al., 2006; Kassan et al., 2010). The cardioprotective and antioxidant effect of pravastatin was further confirmed by the fact that treatment with pravastatin showed prevention of impaired NO-dependent vasodilation and NADPH oxidase-mediated-ROS generation by blocking the down-regulation of Akt/eNOS pathways in rats (Ohkawara et al., 2010). Furthermore, administration of pravastatin showed cardioprotection in rats as assessed by better recovery of cardiac function (improvement in heart rate, left ventricular developed pressure, coronary flow and coronary resistance,) less release of biomarkers of cardiac injury (lactate dehydrogenase, creatine kinase-MB and endothelin1) and attenuation of ventricular arrhythmias (ventricular tachyarrhythmia and ventricular fibrillation) (Li et al., 2010). Chronic use of pravastatin after infarction resulted in enhanced connexin-43 quantity by attenuating mevalonatedependent ET-1 production through PKC-dependent pathway confirming its antiarrythmic effect in rats (Chen et al., 2010). Additionally, pravastatin has been reported to significantly reduce the cardiac AT-II levels and angiotensin converting enzyme 1 and 2 expressions normalizing the cardiac sympathetic hyper-responsiveness in rats confirming its potent cardioprotective effect (Herring et al., 2010).
2. Pravastatin and cardioprotection Pravastatin, a member of the drug class known as statins, chemically is (3R,5R)-3,5-dihydroxy-7-((1R,2S,6S,8R,8aR)-6hydroxy-2-methyl-8-{[(2S)-2-methylbutanoyl]oxy}-1,2,6,7,8,8ahexahydronaphthalen-1-yl)-heptanoic acid (Fig. 2). It has been noted that the pravastatin therapy improved the endotheliumdependent coronary vasomotion that contributed in the improvement of myocardial perfusion as well as regression of coronary atherosclerosis. Treatment with pravastatin prevented the reperfusion-induced ventricular tachycardia and ventricular fibrillation in rats that evidenced its beneficial role in decreasing cardiovascular mortality (Chen et al., 2003). Moreover, pravastatin treatment has been noted to prevent cardiovascular remodeling in the spontaneous diabetic rat model by increasing the expression of cardiac eNOS and inhibiting the over expressions of fibrogenic/proinflammatory cytokines (Yu et al., 2004). Pravastatin treatment prevented cardiomyocyte cell death following simulated hypoxia and reoxygenation by increasing NO release, decreasing myocyte endothelin-1 (ET-1) production and increasing Akt phosphorylation that demonstrated the novel protective role of pravastatin in human ventricular cardiomyocytes independent of endothelial cells types (Verma et al., 2004; Favaro et al., 2008). Statin therapy may restore ischemic hearts to full functional integrity during cardioplegic arrest through a direct effect on cardiomyocyte survival showing its potential in attenuating heart failure (Verma et al., 2004; Bezerra and Mandarim-de-Lacerda, 2005; Reddy et al., 2005). Moreover, pravastatin has been noted to exert antihypertropic effects by activation of KATP channels resulting in the amelioration of cardiomyocyte hypertrophy in rabbits (Lee et al., 2004). Pravastatin administration improved flow-mediated dilatation revealing its pleiotropic effects during the early phase of acute coronary syndrome. In addition, the circulating lipid peroxidation products in patients with unstable angina decreased significantly with pravastatin therapy (Cannon et al., 2004; Karatzis et al., 2005; Ky et al., 2008). The antioxidant effect of pravastatin was further confirmed by the fact that pravastatin in combination with pioglitazone modulated ANG II-mediated oxidative stress, inhibiting mitogen-activated protein kinase (MAPK) and NF-jB activation in mice (Chen and Mehta, 2006). Further, administration of pravastatin attenuated left
Figure 2
Chemical structure of pravastatin.
3. Atorvastatin and cardioprotection Atorvastatin, another member of the drug class known as statins, chemically is (3R,5R)-7-[2-(4-fluorophenyl)-3-phenyl-4(phenylcarbamoyl)-5-(propan-2-yl)-1H-pyrrol-1-yl]-3,5-dihydroxyheptanoic acid (Fig. 3). It has been noted that atorvastatin treatment produced endothelium-dependent vasodilation and improved endothelial dysfunction in rats by decreasing oxidative stress (Aviram et al., 1998; Perticone et al., 2000). Atorvastatin showed protective effect in heart which is mediated by an increase in eNOS expression and thereby increase in NO bioavailability (Birnbaum et al., 2003). Administration with atorvastatin significantly reduced thiobarbituric acid reactive oxygen substances (TBARS) levels and lipid peroxide concentrations as well as increased the reduced glutathione levels, the oxidative stress markers, which further evidenced its antioxidant action (Mahfouz and Kummerow, 2005; Ozacmak et al., 2007). It has been widely accepted that myocardial injury is associated with increased oxidative stress which involves
Figure 3
Chemical structure of atorvastatin.
Please cite this article in press as: Rohilla, A. et al., Pleiotropic effects of statins: A boulevard to cardioprotection. Arabian Journal of Chemistry (2011), doi:10.1016/j.arabjc.2011.06.025
4 NADPH oxidase. Atorvastatin treatment reduced vascular and cardiac free radical formation, normalized the expression of the NADPH oxidase and showed anti-oxidative properties along with enhancement of NO synthesis (Mahfouz and Kummerow, 2005; Bolayirli et al., 2007). Moreover, administration of isoproterenol produced severe myocardial damage and oxidative stress in rats. Atorvastatin treatment reduced myocardial infarction in rat hearts as assessed in terms of improvement in serum parameters, ATPase activities and reduction in oxidative stress. The lipid-independent anti-oxidative and anti-inflammatory effects of atorvastatin involve ERK1/2/NF-jB-pathway that is noted to afford cardioprotection (Riad et al., 2007). Moreover, the decrease in oxidative stress in subjects with metabolic syndrome was also noted with atorvastatin treatment (Singh et al., 2008). Atorvastatin has been reported to induce a significant decrease in TNF-a, IL-6 and MDA along with a significant increase of SOD activity that accounts for its cardioprotective and antioxidant action (Castro et al., 2008). High-fat diets significantly increased the C-reactive protein (CRP) levels and oxidative stress and compromised mitochondrial response to ischemia that was found to be reversed by atorvastatin treatment in a high-fat diet rat model which provide a superior control of cardiovascular risk markers in diabetic and hyperlipidemic subjects (Matafome et al., 2008). Moreover, atorvastatin has been noted to reduce systemic oxidative stress by direct inhibition of protein oxidation and oxidative DNA damage (Aydin et al., 2009). Additionally, atorvastatin treatment reduced electrophysiological alteration induced by I/R in isolated rat hearts as assessed in terms of prolonging the effective refractory period mediated by activation of NO pathway ultimately enhancing the myocardial electrophysiological stability (Xu et al., 2010a,b). Furthermore, recent studies have demonstrated that atorvastatin inhibited homocysteine-induced NADPH oxidase activation, ROS accumulation and apoptosis through p38MAPK dependent mechanisms that contribute to atorvastatin-mediated card protective effects (Bao et al., 2010). An interesting study confirmed the cardioprotective effect of atorvastatin as assessed by restoration of the infarct size-limiting and contractile dysfunction-reducing effect of ischemic postconditioning in rat hearts, the mechanism of which involved increased phosphorylation of Akt and eNOS (Ying et al., 2010). Clinically, treatment of atorvastatin inhibited oxidative stress by adiponectin-mediated NADPH oxidase down-regulation in hypercholesterolemic patients that further evidenced atorvastatin’s antioxidant effect. The cardioprotective potential of atorvastatin was further confirmed by the fact that atorvastatin treatment reversed hypertension-induced cardiac remodeling in rats by down-regulating PKD and myocyte enhancer factor which may serve as a novel therapeutic target for atorvastatin in treating hypertensive patients (Bacova et al., 2010; Geng et al., 2010). 4. Simvastatin and cardioprotection Simvastatin, third member of the statins class, chemically is (1S,3R,7S,8S,8aR)-8-{2-[(2R,4R)-4-hydroxy-6-oxooxan-2yl]ethyl}-3,7-dimethyl-1,2,3,7,8,8a-hexahydrona phthalen-1yl-2,2-dimethylbutanoate (Fig. 4). Simvastatin is a potent cardioprotective agent that inhibit leukocyte endothelial cell interactions and preserve cardiac contractile function and
A. Rohilla et al.
Figure 4
Chemical structure of simvastatin.
coronary perfusion after myocardial I/R and this effect is mediated by enhanced endothelial release of NO (Lefer et al., 1999; Di Napoli et al., 2001). The cardioprotective effect of simvastatin in a model of I/R in the Langendorff rat heart has been reported as assessed in terms of increased eNOS expression and thereby increased NO bioavailability (Di Napoli et al., 2001). The leukocytic and aortic productions of ROS along with protein and lipid oxidation products such as TBARS were prevented in an experimental model by simvastatin confirming its antioxidant effect (Delbosc et al., 2002). It ahs been reported that simvastatin improved the erythrocyte filterability in patients with familial hypercholesterolemia evidencing its potential cardioprotective role in clinical patients (Koter et al., 2003). In addition, experimental studies have shown that administration of simvastatin attenuated the oxidative stress and afforded cardioprotection by decreasing MDA levels and increasing the SOD and NO levels (Bayorh et al., 2005; Yin et al., 2007). Further, treatment with simvastatin was noted to be effective in reducing the oxidative stress and infarction volume that was responsible for ameliorating ischemic damage in rats. It ahs been reported that simvastatin pretreatment significantly reduced reperfusion arrhythmias occurring after regional ischemia in an open chest diabetic-hypercholesterolemic rat model (Adameova´ et al., 2006). Simvastatin reduced the activity of NADPH-CoQ reductase, an enzyme required in generation of free radicals that further evidenced its potent role as an antioxidant (Kettawan et al., 2007). Clinical studies have also suggested the cardioprotective role of simvastatin in patients undergoing cardiopulmonary bypass surgery by showing significant beneficial effects by decreasing lipid peroxidation (Coccia et al., 2007). Moreover, the treatment with simvastatin has been noted to possess antioxidant effect in diabetic-hypercholesterolemic rats (Kuzelova´ et al., 2008). Furthermore, simvastatin treatment significantly improved endothelial function and reduced oxidative stress that evidenced its antioxidant action in order to afford cardioprotection (Tong et al., 2009). Decrease in postischemic recovery of left ventricular developed pressure, increase in ventricular fibrillation, lengthening the duration of ventricular tachycardia and increase in myocardial infarct size are the markers of myocardial damage that was found to be reversed by simvastatin treatment that confirmed its pleiotropic in both healthy and diseased individuals (Adameova et al., 2009). Additionally, simvastatin has been recently reported to significantly reduce total cholesterol, triglycerides, low density lipoproteins, conjugated diene, total peroxide, and malondialdehyde levels that further evidenced its potential role as antioxidant and cardioprotective agent (Kumar, 2010).
Please cite this article in press as: Rohilla, A. et al., Pleiotropic effects of statins: A boulevard to cardioprotection. Arabian Journal of Chemistry (2011), doi:10.1016/j.arabjc.2011.06.025
Pleiotropic effects of statins: A boulevard to cardioprotection
Figure 5
Chemical structure of rosuvastatin.
5. Rosuvastatin and cardioprotection Rosuvastatin, the latest member of statins class, chemically is (3R,5S,6E)-7-[4-(4-fluorophenyl)-2-(N002Dmethylmethanesulfonamido)-6-(propan-2-yl)pyrimidin-5-yl]-3,5-dihydroxyhept-6enoic acid (Fig. 5). It has been reported that treatment with rosuvastatin increased vascular endothelial NO production and attenuated myocardial necrosis following I/R in mice evidencing its potential cardioprotective effect (Jones et al., 2002). Moreover, rosuvastatin given 18 h before I/R has significantly improved left ventricular developed pressure and the maximal rate of development of left ventricular developed pressure in a rat model of I/R which provide evidence that rosuvastatin significantly attenuated cardiac contractile dysfunction in isolated perfused rat hearts (Ikeda et al., 2003). Administration with rosuvastatin has been noted to reduce arterial pressure in genetic hypertension and improve systemic and regional hemodynamics in hypertensive rat hearts confirming its potent cardioprotective role (Susic et al., 2003; Neto-Ferreira et al., 2011). In addition, it has been demonstrated that rosuvastatin exerted potent antioxidative effects which were capable of preventing DNA damage in vivo by involving the induction of the expression of antioxidant defense enzymes (Grosser et al., 2004; Schupp et al., 2008). Further, chronic treatment with rosuvastatin before ischemia reduced I/R injury in rat hearts and prevented coronary endothelial cell and cardiomyocyte damage by NO-dependent mechanisms (Di Napoli et al., 2005). Rosuvastatin significantly reduced infarct size in mice hearts after 60 min of I/R suggesting its potential as a cardioprotective agent as assessed by reduction in neutrophil infiltration and increasing the expression of eNOS and thereby increasing NO production (Weinberg et al., 2005). Additionally, rosuvastatin treatment has been reported to normalize the endothelial function and reduce the platelet activation in diabetic rats which may contribute to the reduction of cardiovascular events by statins in diabetic patients (Scha¨fer et al., 2007). The normalization of ROS production and platelet aggregation in a hamster model by rosuvastatin treatment has further confirmed its potential as a vasculoprotective and cardioprotective agent (Miersch et al., 2007; Almeid et al., 2009). The elevations of left ventricular wet weight, myocardial extracellular matrix content, diastolic stiffness, and alterations in systolic and diastolic function are the markers of heart failure that were noted to be inhibited by chronic rosuvastatin treatment in rat hearts (Loch et al., 2009). Furthermore, rosuvastatin treatment showed a protective role in rat model of left ventricular hypertrophy as assessed in terms of attenuation of myocardial fibrosis and left ventricular stiffness (Chang et al., 2009). Rosuvastatin treatment was noted to reduce plasma concentrations of total cholesterol, low density lipoproteins
5 and triglycerides, urine and plasma oxidative stress markers and plasma CRP in hypercholesterolemic patients that further evidenced its antioxidant effect (Yoshino et al., 2009; Koksal et al., 2010). It has been recently reported that rosuvastatin in combination with standard heart failure therapy results in a significant additional improvement in heart failure and cardiac remodeling in rats confirming its potent cardioprotective effect (Go´mez-Garre et al., 2010; Ying et al., 2010). In addition, short-term treatment with rosuvastatin significantly increased the number of circulating endothelial progenitor cells in patients with heart failure that further confirmed its antioxidant and cardioprotective effect providing further insights into its role in these individuals (Tousoulis et al., 2011). 6. Conclusion Accumulating evidence indicates that statin therapy favorably influences a number of diverse clinical events through both effects related to lowering of cholesterol levels and effects independent of the lowering of cholesterol levels. The latter effects are referred to as pleiotropic. The pleiotropic effects of the statins improve vascular relaxation, promote new vessel formation, inhibit platelet aggregation and reducing vascular inflammation. It is noteworthy that the pleiotropic properties of the statins have been beneficial in a variety of diseases that involve a number of organs and organ systems. By enhancing eNOS expression and thereby increasing NO bioavailability, reducing oxidative stress and proinflammatory cytokine production and preventing ROS production and apoptosis, the HMG-CoA reductase inhibitors may prove to be useful agents in treating patients with cardiovascular diseases. The findings of this study, therefore, may have important clinical implications since cardiovascular diseases are a major cause of morbidity and mortality worldwide. Moreover, the observations that acute exposure to statins may also afford cardioprotection imply their potential use in situations of controlled, deliberate myocardial I/R, such as coronary angioplasty, coronary artery by-pass grafting and cardiac transplantation that would open new doors for the treatment strategies of such patients. The beneficial role of statins in the experimental setting of myocardial I/R injury would surely open new gates in the treatment of patients presented with coronary heart disease. The clinical relevance of these effects is beginning to be recognized and further studies would be able to answer such questions in the near future. References Abe, Y., Izumi, T., Urabe, A., Nagai, M., Taniguchi, I., Ikewaki, K., Mochizuki, S., 2006. Cardiovasc. Drug Ther. 20, 273–280. Adameova´, A., Kuzelova´, M., Faberova´, V., Svec, P., 2006. Pharmazie 61, 807–808. Adameova, A., Harcarova, A., Matejikova, J., Pancza, D., Kuzelova, M., Carnicka, C., Svec, P., Bartekova, M., Styk, J., Ravingerova´, T., 2009. Physiol. Res. 58, 449–454. Almeid, E.A., Hernandes, D.B., Ozaki, M.R., Ramı´ rez-Nu´n˜ez, W.R., 2009. Arteriosclerosis 21, 263–267. Alvarez de Sotomayor, M., Herrera, M.D., Marhuenda, E., Andriantsitohaina, R., 2000. Br. J. Pharmacol. 131, 1179–1187. Aviram, M., Rosenblat, M., Bisgaier, C.L., Newton, R.S., 1998. Atherosclerosis 138, 271–280. Aydin, S., Uzun, H., Sozer, V., Altug, T., 2009. Pharmacol. Res. 59, 242–247.
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Please cite this article in press as: Rohilla, A. et al., Pleiotropic effects of statins: A boulevard to cardioprotection. Arabian Journal of Chemistry (2011), doi:10.1016/j.arabjc.2011.06.025