Hypercholesterolaemia and hypertension are major public health problems that are frequently treated with statins and renin-angiotensin system (RAS) blockades. Although the mechanisms of action for these two classes of drugs differ, both classes have beneficial effects on the vasculature. Experimental and clinical studies demonstrated that combined statins and RAS blockades improve endothelial function as reflected by improved flow-mediated dilation, improved fibrinolysis potential and reduced oxidant stress, inflammatory markers and insulin sensitivity. There is a strong scientific rationale for recommending combination therapy, especially statins and RAS blockades, to treat or prevent atherosclerosis and coronary heart disease. In this article, we address the mechanisms on the cross-talk between statins and RAS and discuss the rationale and importance of combination therapy with statins and RAS blockades in treating and preventing cardiovascular events.
Systemic hypertension, hypercholesterolaemia and diabetes are associated with endothelial dysfunction that promotes inflammation, oxidation of lipoproteins, smooth-muscle proliferation, extracellular matrix deposition or lysis, accumulation of lipid-rich material, platelet activation, thrombus formation and insulin resistance. All of these consequences of endothelial dysfunction and insulin resistance may contribute to the development and clinical expression of atherosclerosis.1 Hypercholesterolaemia and hypertension are major public health problems that are frequently treated with statins and renin-angiotensin system (RAS) blockades. Although the mechanisms of action for these two classes of drugs differ, both classes have beneficial effects on the vasculature. Indeed, large-scale clinical studies have demonstrated that statins and RAS blockades prevent and retard the progression of coronary heart disease.2,3 An important emerging concept for prevention or treatment of atherosclerosis is that pathophysiological cross-talk between risk factors may be effectively addressed by combination therapy that simultaneously targets several risk factors and addresses multiple molecular mechanisms.4-6 In this article, we address the mechanisms that control the cross-talk between statins and RAS and discuss the rationale and importance of combination therapy with statins and RAS blockades in treating and preventing cardiovascular events.
Basic Mechanisms and Pre-clinical Evidence In Terms of Cross-talk Between Statin and the Renin-angiotensin System
Statins reduce low-density lipoprotein (LDL) cholesterol and improve endothelial function via stimulation of nitric oxide (NO) synthase activity, and mediate antioxidant effects that result in enhanced NO bioactivity.7,8 In addition, statins have antioxidative effects via indirect NO inhibitory action through inhibition of Rac isoprenylation and attenuate oxidative stress through inhibition of Rac1.9 Atorvastatin protects against cerebral infarction via inhibition of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase-derived superoxide in transient focal ischaemia.10 Cerivastatin may act by inhibiting the prenylation, membrane anchoring and subsequent activation of Ras proteins.11 Lovastatin also stimulates protein kinase B/Akt kinase activity, and Akt-dependent phosphorylation forces p21 in the cytoplasm where it inhibits Rho-kinases contributing to the suppression of cardiomyocyte hypertrophy.12
RAS blockades also improve endothelial function.13,14 A potential mechanism of this effect is augmented NO bioactivity via diminished bradykinin degradation by angiotensin-converting enzyme (ACE) with activation of endothelial B2 kinin receptors and stimulation of NO synthase activity.15 Alternatively, ACE inhibition may diminish intracellular production of superoxide anions via reduced activity of angiotensin II-dependent oxidases in the endothelium and vascular smooth muscle,16,17 thus protecting NO from oxidant degradation to biologically inert or toxic molecules.18 Inhibition of the production of superoxide anions may also limit the oxidation of LDL, thus contributing to increased NO bioactivity by enhancing NO synthesis and limiting oxidative degradation of NO.18,19 These studies suggest that angiotensin II promotes superoxide anion generation and endothelial dysfunction. This effect is mediated by the angiotensin II type 1 (AT1) receptor. Angiotensin II activates the nuclear transcription factor nuclear factor kappa B (NFκB), which is induced by oxidative stress.20 NFκB activates pro-inflammatory transcription factors and thus stimulates the synthesis of protein products, such as cell adhesion molecules and chemokines.20,21 On the other hand, angiotensin II stimulates the expression of plasminogen activator inhibitor-1 (PAI-1) antigen released from endothelial cells and ACE inhibitor may diminish a potent stimulus (angiotensin II) for PAI-1 synthesis by the endothelium,22 thus potentiating fibrinolysis. In addition, C-reactive protein (CRP) upregulates AT1 receptors in vascular smooth-muscle cells and these effects are attenuated by losartan.23 Indeed, ACE inhibitors inhibit LDL oxidation and attenuate atherosclerosis.24Figure 1 represents the basic mechanisms of cross-talk between statins and RAS blockades on improving endothelial function.
The additional beneficial effects of combined statins and RAS blockades may be the result of several interacting mechanisms. For example, angiotensin II is a potent endogenous vasoconstrictor, while LDL induces upregulation of the AT1 receptor.25 Hypercholesterolaemic rabbits display enhanced vascular expression of AT1 receptors that mediate increased activity of angiotensin II.26 Furthermore, the effect of statins to reverse the elevated blood pressure response to angiotensin II infusion is accompanied by downregulated AT1 receptor density.27,28 Indeed, in apolipoprotein E (ApoE) null mice fed with a high-cholesterol diet, neither valsartan nor fluvastatin had any effect on blood pressure or cholesterol level; however, combined therapy with both drugs decreases plaque area and lipid deposition after 10 weeks.29
Clinical Evidences of Cross-talk Between Statins and the Renin-angiotensin System
We reported additive beneficial effects of combined therapy with statins and RAS blockades on vascular and metabolic responses compared with those of either statin and RAS blockade alone in patients with cardiovascular risk factors.30-33 Losartan alone, simvastatin alone or combined therapy with losartan and simvastatin significantly improved flow-mediated dilator response to hyperaemia (marker of endothelial function) and decreased plasma oxidant stress and inflammatory marker relative to baseline measurements. However, these parameters were changed to a greater extent with combined therapy compared with simvastatin or losartan alone (see Figure 2). Of interest, combined therapy or losartan alone significantly increased plasma adiponectin levels and insulin sensitivity relative to baseline measurements (see Figure 3). These changes were significantly greater than those observed in the group treated with simvastatin alone. This study demonstrated that simvastatin combined with losartan improved endothelial function, reduced inflammatory markers and improved insulin sensitivity to a greater extent than monotherapy with either drug in hypertensive, hypercholesterolaemic patients.30,31
In our study, additive beneficial effects of combined therapy with statin and the ACE inhibitor ramipril were demonstrated in hypercholesterolaemic and patients with type 2 diabetes.32 Ramipril alone, simvastatin alone or combined therapy with ramipril and simvastatin treatment arms significantly improved flow-mediated dilator response to hyperaemia and reduced plasma levels of malondialdehyde (oxidative stress marker) relative to baseline measurements. However, these parameters were changed to a greater extent with combined therapy compared with either simvastatin or ramipril alone. Combined therapy or ramipril alone significantly increased plasma adiponectin levels and insulin sensitivity relative to baseline measurements compared with simvastatin or ramipril alone, combined therapy significantly reduced high-sensitivity CRP levels. Interestingly. In addition, combined therapy with ramipril and simvastatin had beneficial additive effects on tissue factor activity and prothrombin fragment 1+2 in patients with type 2 diabetes.33
These beneficial effects of combined statins with RAS blockades on endothelial function, inflammation and oxidative stress were confirmed by others. Twenty patients with type 2 diabetes took atorvastatin, irbesartan or both for one week. High-fat load and glucose alone produced a decrease in endothelial function and an increase in inflammation. These effects were more pronounced when high-fat load and glucose were combined. Short-term atorvastatin and irbesartan treatments significantly counterbalanced these phenomena, and their combination was more effective than either therapy alone.34 On-pump coronary artery bypass graft surgery is associated with an intense systemic inflammatory response that is almost completely prevented by early treatment with high doses of ACE inhibitors and statins.35 In a small, randomised, open-label study, combined therapy with rosuvastatin and telmisartan had favourable effects on homeostatic model assessment of insulin resistance (HOMA-IR), fasting serum insulin and high-sensitivity CRP (hs-CRP) compared with the rosuvastatin combined with irbesartan and rosuvastatin combined with olmesartan in Greek adults with impaired fasting glucose, mixed hyperlipidaemia and stage 1 hypertension. This study may suggest that AT1 receptor blocker (ARB), which has partial activator effect of peroxisome proliferator-activated receptor gamma (PPARgamma), would be more favourable on metabolic parameters when combined with statins.36
Clinical Perspectives of Cross-talk Between Statins and the Renin-angiotensin System
Impaired endothelial vasodilation is associated with increased cardiovascular event rates. Furthermore, endothelial dysfunction and increased vascular oxidative stress, inflammation and fibrinolysis status predict the risk of cardiovascular event rates in patients with coronary artery disease.37,38 Combined statins and RAS blockades improve endothelial function as reflected by improved flow-mediated dilation, improves fibrinolysis potential and reduced oxidant stress, inflammatory markers and insulin sensitivity. Recently, reciprocal relationships between endothelial dysfunction and insulin resistance have been proposed.1,39 In addition, there are some debates on unfavourable effects of statins on insulin sensitivity and development of diabetes.40-42 In terms of this important matter, combined therapy with statins and RAS blockades may improve insulin sensitivity and aid prevention of the development of new diabetes in patients at high risk of cardiovascular disease compared with statins alone.
In conclusion, there is a strong scientific rationale for recommending combination therapy, especially statins and RAS blockades to treat or prevent atherosclerosis and coronary heart disease.43,44 Combined therapy with statins and RAS blockades may be an important emerging concept in developing optimal treatment and prevention strategies for atherosclerosis, coronary heart disease and co-morbid metabolic disorders characterised by endothelial dysfunction and insulin resistance. In the future, randomised trials are needed to gain additional insight into the extent that combination therapy may be superior to monotherapy.
- Han SH, Quon MJ, Koh KK, Reciprocal relationships between abnormal metabolic parameters and endothelial dysfunction, Curr Op Lipidol, 2007;18:58-65.
- Heart Protection Study Collaborative Group, MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebo-controlled trial, Lancet, 2002;360:7-22.
- Dahlof B, Devereux RB, Kjeldsen SE, et al; The LIFE Study Group., Cardiovascular morbidity and mortality in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE): a randomised trial against atenolol, Lancet, 2002;359:995-1003.
- Kim JA, Koh KK, Quon MJ, The union of vascular and metabolic actions of insulin in sickness and in health, Arterioscler Thromb Vasc Biol, 2005;25:889-91.
- Koh KK, Han SH, Quon MJ, Inflammatory markers and the metabolic syndrome: insights from therapeutic interventions, J Am Coll Cardiol, 2005;46:1978-85.
- Han SH, Quon MJ, Kim J, Koh KK, Adiponectin and cardiovascular disease: Response to therapeutic interventions, J Am Coll Cardiol, 2007;49:531-8.
- Koh KK, Effects of statins on vascular wall: vasomotor function, inflammation, and plaque stability, Cardiovasc Res, 2000;47:648-57.
- Koh KK, Cardillo C, Bui MN, et al., Vascular effects of estrogen and cholesterol-lowering therapies in hypercholesterolemic postmenopausal women, Circulation, 1999;99:354-60.
- Nakagami H, Jensen KS, Liao JK, A novel pleiotropic effect of statins: prevention of cardiac hypertrophy by cholesterolindependent mechanisms, Ann Med, 2003;35:398-403.
- Hong H, Zeng JS, Kreulen DL, et al., Atorvastatin protects against cerebral infarction via inhibiting NADPH oxidasederived superoxide in ischemic stroke, Am J Physiol Heart Circ Physiol, 2006;291:H2210-5.
- Dechend R, Fiebler A, Lindschau C, et al., Modulating angiotensin II-induced inflammation by HMG Co-A reductase inhibition, Am J Hypertens, 2001;14(6 Pt 2):55S-61S.
- Hauck L, Harms C, Grothe D, et al., Critical role for FoxO3adependent regulation of p21CIP1/WAF1 in response to statin signaling in cardiac myocytes, Circ Res, 2007;100:50-60.
- Koh KK, Ahn JY, Han SH, et al., Pleiotropic effects of angiotensin II receptor blocker in hypertensive patients, J Am Coll Cardiol, 2003;42:905-10.
- Prasad A, Tupas-Habib T, Schenke WH, et al., Acute and chronic angiotensin-1 receptor antagonism reverses endothelial dysfunction in atherosclerosis, Circulation, 2000;101:2349-54.
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- Mohazzab KM, Kaminski PM, Wolin MS, NADH oxidoreductase is a major source of superoxide anion in bovine coronary artery endothelium, Am J Physiol, 1994;266:H2568-72.
- Nickenig G, Harrison DG, The AT1-type angiotensin receptor in oxidative stress and atherogenesis: part I: oxidative stress and atherogenesis, Circulation, 2002;105:393-6.
- Koh KK, Oh PC, Quon MJ, Does reversal of oxidative stress and inflammation provide vascular protection?, Cardiovasc Res, 2009;81:649-59.
- Pueyo ME, Gonzalez W, Nicoletti A, et al., Angiotensin II stimulates endothelial vascular cell adhesion molecule-1 via nuclear factor-kappaB activation induced by intracellular oxidative stress, Arterioscler Thromb Vasc Biol, 2000;20:645-51.
- Zeiher AM, Fisslthaler B, Schray-utz B, Busse R, Nitric oxide modulates the expression of monocyte chemoattractant protein 1 in cultured human endothelial cells, Circ Res, 1995;76:980-6.
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- Wang CH, Li SH, Weisel RD, et al., C-reactive protein upregulates angiotensin type 1 receptors in vascular smooth muscle, Circulation, 2003;107:1783-90.
- Hayek T, Attias J, Coleman R, et al., The angiotensinconverting enzyme inhibitor, fosinopril, and the angiotensin II receptor antagonist, losartan, inhibit LDL oxidation and attenuate atherosclerosis independent of lowering blood pressure in apolipoprotein E deficient mice, Cardiovasc Res, 1999;44:579-87.
- Nickenig G, Sachinidis A, Michaelsen F, et al., Upregulation of vascular angiotensin II receptor gene expression by lowdensity lipoprotein in vascular smooth muscle cells, Circulation, 1997;95:473-8.
- Nickenig G, Jung O, Strehlow K, et al., Hypercholesterolemia is associated with enhanced angiotensin AT1-receptor expression, Am J Physiol, 1997;272:H2701-7.
- Nickenig G, Baumer AT, Temur Y, et al., Statin-sensitive dysregulated AT1 receptor function and density in hypercholesterolemic men, Circulation, 1999;100:2131-4.
- Dechend R, Fiebeler A, Park JK, et al., Amelioration of angiotensin II-induced cardiac injury by a 3-hydroxy-3- methylglutaryl coenzyme a reductase inhibitor, Circulation, 2001;104:576-81.
- Li Z, Iwai M, Wu L, et al., Fluvastatin enhances the inhibitory effects of a selective AT1 receptor blocker, valsartan, on atherosclerosis, Hypertension, 2004;44:758-63.
- Koh KK, Quon MJ, Han SH, et al., Additive beneficial effects of losartan combined with simvastatin in the treatment of hypercholesterolemic, hypertensive patients, Circulation, 2004;110:3687-92.
- Han SH, Koh KK, Quon MJ, et al., The effects of simvastatin, losartan, and combined therapy on soluble CD40 ligand in hypercholesterolemic, hypertensive patients, Atherosclerosis, 2007;190:205-11.
- Koh KK, Quon MJ, Han SH, et al. Vascular and metabolic effects of combined therapy with ramipril and simvastatin in patients with type 2 diabetes, Hypertension, 2005;45:1088-93.
- Koh KK, Quon MJ, Han SH, et al., Combined therapy with ramipril and simvastatin has beneficial additive effects on tissue factor activity and prothrombin fragment 1+2 in patients with type 2 diabetes, Atherosclerosis, 2007;194:230-7.
- Ceriello A, Assaloni R, Da Ros R, et al., Effect of atorvastatin and irbesartan, alone and in combination, on postprandial endothelial dysfunction, oxidative stress, and inflammation in type 2 diabetic patients, Circulation, 2005;111:2518-24.
- Radaelli A, Loardi C, Cazzaniga M, et al., Inflammatory activation during coronary artery surgery and its dosedependent modulation by statin/ACE-inhibitor combination, Arterioscler Thromb Vasc Biol, 2007;27:2750-5.
- Rizos CV, Milionis HJ, Kostapanos MS, et al., Effects of rosuvastatin combined with olmesartan, irbesartan, or telmisartan on indices of glucose metabolism in Greek adults with impaired fasting glucose, hypertension, and mixed hyperlipidemia: a 24-week, randomized, open-label, prospective study, Clin Ther, 2010;32:492-505.
- Halcox JPJ, Schenke WH, Zalos G, et al., Prognostic value of coronary vascular endothelial dysfunction, Circulation, 2002;106:653-8.
- Heitzer T, Schlinzig T, Krohn K, et al., Endothelial dysfunction, oxidative stress, and risk of cardiovascular events in patients with coronary artery disease, Circulation, 2001;104:2673-8.
- Kim J, Montagnani M, Koh KK, Quon MJ, Reciprocal relationships between insulin resistance and endothelial dysfunction: molecular and pathophysiological mechanisms, Circulation, 2006;113:1888-904.
- Ridker PM, Danielson E, Fonseca FA, et al., Rosuvastatin to prevent vascular events in men and women with elevated Creactive protein, N Engl J Med, 2008;359:2195-2207.
- Sattar N, Preiss D, Murray HM, et al., Statins and risk of incident diabetes: a collaborative meta-analysis of randomized statin trials, Lancet, 2010;375:735-42.
- Cannon CP, Balancing the benefits of statins versus a new risk-diabetes, Lancet, 2010;375:700-1.
- Koh KK, Combination treatment to prevent atherosclerosis, Hypertension, 2007;50:e67.
- Koh KK, Quon MJ, Combination therapy for treatment or prevention of atherosclerosis, Hypertension, 2008;52:e18.