Pleiotropic effects of statins. - Basic research and clinical perspectives -

Qian Zhou, James K Liao, Qian Zhou, James K Liao

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 suggests 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, may be a predominant mechanism contributing to the pleiotropic effects of statins. The aim of the present review is to 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.

Figures

Figure 1. Biological actions of isoprenoids
Figure 1. Biological actions of isoprenoids
Statins inhibit HMG-COA reductase acitivity and decreases the isoprenylation of intracellular signaling molecules, such as RhoA, Rac1 and Cdc42.
Figure 2. Regulation of the Rho GTPase…
Figure 2. Regulation of the Rho GTPase cycle
Rho protein cycle between an inactive GDP-bound and an active GTP-bound state. Inhibition of the mevalonate synthesis by statins prevents memrbane targeting of Rho and its subsequent activation of ROCK. The inhibition of the Rho/ROCK pathway may mediate some of the pleiotropic effects of statins on the vascular wall.
Figure 3. Upregulation of eNOS by statins
Figure 3. Upregulation of eNOS by statins
Statins modulate eNOS expression through three major mechanisms: 1) Increased eNOS mRNA stability through inhibition of Rho isoprenylation. 2) Increased eNOS phosphorylation through PI3K-dependent signaling. 3) Restoration of eNOS activity through reduction of caveolin-1 abundance.

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