Pleiotropic Effects of Statins - Basic Research and Clinical Perspectives -

Abstract

Statins are 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, which are widely used to lower serum cholesterol levels in the primary and secondary prevention of cardiovascular disease. Recent experimental and clinical evidence suggest that the beneficial effects of statins may extend beyond their cholesterol lowering effects, to include so-called pleiotropic effects. These cholesterol-independent effects include improving endothelial function, attenuating vascular and myocardial remodeling, inhibiting vascular inflammation and oxidation, and stabilizing atherosclerotic plaques. The mechanism underlying some of these pleiotropic effects is the inhibition of isoprenoid synthesis by statins, which leads to the inhibition of intracellular signaling molecules Rho, Rac and Cdc42. In particular, inhibition of Rho and one of its downstream targets, Rho kinase (ROCK), may be a predominant mechanism contributing to the pleiotropic effects of statins. In this review, we provide an update on the non-cholesterol-dependent statin effects in the cardiovascular system and highlight some of the recent findings from bench to bedside to support the concept of statin pleiotropy.

Add-On Effect of Probucol in Atherosclerotic, Cholesterol-Fed Rabbits Treated with Atorvastatin

“…Such antioxidative effects of probucol might be more important than its free radical scavenging activity in terms of the prevention of atherosclerosis. Although statins are also reported to have such anti-oxidative effects (i.e., an increase in heme oxygenase-1 expression and a decrease in NAD(P)H oxidase activity [19]), probucol but not atorvastatin decreased the plasma and plaque OxLDL levels, indicating the antioxidative effect of probucol differs in vivo from that of atorvastatin. Previous work found that plasma OxLDL levels in apolipoprotein E-knockout mice measured by our sandwich ELISA procedure preceded the formation of extensive atherosclerotic lesions, suggesting that OxLDL has pro-atherosclerotic properties in vivo [22].…”

“…These drugs also have various antiinflammatory activities [13], [19]. Plasma CRP concentration is a clinically important marker of increased risk of cardiovascular disease, and CRP concentration in rabbits is increased by feeding a cholesterol-enriched diet for longer than 12 weeks [26].…”

“…Several studies in animals [17] and in humans [18] have examined the effects of probucol combined with statins on atherosclerosis; however, these reports did not compare the effect of combined therapy to that of monotherapy. Both drugs also possess other anti-atherogenic effects such as antiinflammatory effects [13], [19]; therefore, it remains unclear whether probucol combined with statins would have a significant add-on effect in the treatment of atherosclerosis without interfering with the pleiotropic effects of these drugs.…”

Effects of simvastatin/ezetimibe on microparticles, endothelial progenitor cells and platelet aggregation in subjects with coronary heart disease under antiplatelet therapy

“…The pleiotropic effects of statin therapy include increased nitric oxide bioavailability, antithrombotic, and anti-inflammatory effects (9,10). However, the benefits of vascular protection may vary according to the potency of statin or pharmacokinetic interactions.…”

Effect of rosuvastatin on hyperuricemic rats and the protective effect on endothelial dysfunction

“…A third mechanism reported hypothesizes that statins regulate the activity of eNOS via their effects on caveolin-1. Caveolin-1 is an integral membrane protein that binds to eNOS in caveolae, thereby directly inhibiting the production of NO (38). The function of allopurinol, a xanthine oxidase inhibitor, in the prevention and treatment of hyperuricemia was limited due to the inhibitory effect of allopurinol on the biosynthesis of UA, evident only when high levels of UA accumulated in the blood circulation (39).…”