Pleiotropic Effects of Statins on the Cardiovascular System

Abstract

The statins have been used for 30 years to prevent coronary artery disease and stroke. Their primary mechanism of action is the lowering of serum cholesterol through inhibiting hepatic cholesterol biosynthesis thereby upregulating the hepatic low-density lipoprotein (LDL) receptors and increasing the clearance of LDL-cholesterol. Statins may exert cardiovascular protective effects that are independent of LDL-cholesterol lowering called pleiotropic effects. Because statins inhibit the production of isoprenoid intermediates in the cholesterol biosynthetic pathway, the post-translational prenylation of small GTP-binding proteins such as Rho and Rac, and their downstream effectors such as Rho kinase and nicotinamide adenine dinucleotide phosphate oxidases are also inhibited. In cell culture and animal studies, these effects alter the expression of endothelial nitric oxide synthase, the stability of atherosclerotic plaques, the production of proinflammatory cytokines and reactive oxygen species, the reactivity of platelets, and the development of cardiac hypertrophy and fibrosis. The relative contributions of statin pleiotropy to clinical outcomes, however, remain a matter of debate and are hard to quantify because the degree of isoprenoid inhibition by statins correlates to some extent with the amount of LDL-cholesterol reduction. This review examines some of the currently proposed molecular mechanisms for statin pleiotropy and discusses whether they could have any clinical relevance in cardiovascular disease.

Keywords: cardiovascular diseases; cholesterol, LDL; hydroxymethylglutaryl-CoA reductase inhibitors; rho-associated kinases; vascular diseases.

Figure 1

Cholesterol and isoprenoid synthesis pathway which shows the inhibition of 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase by statins. Decrease in isoprenylation of signaling molecules, such as Ras, Rho, and Rac, leads to the modulation of various signaling pathways. ROCK – rho associate protein kinase, NAD(P)H – nicotinamide adenine dinucleotide phosphate, eNOS – endothelial nitric oxide synthase, t-Pa – tissue-type plasminogen activator, ET-1 – endothelin 1, PAI-1 – plasminogen activator inhibitor 1.

Figure 2

The structure and pharmacokinetic properties of the commercially available statins. LDL – low density lipoprotein, T1/2 – half life, h - hours

Figure 3

The predicted reduction in vascular event rate from the JUPITER trial based on its low density lipoprotein (LDL) cholesterol lowering. The gray square represents the average effect of statins versus placebo based on the Cholesterol Treatment Trialists’ collaboration regression line. The individual black squares represent individual trials, the open circle represents the predicted effect of atorvastatin in the Jupiter trial, the black circle represents the observed effect.

Figure 4

Regulation of the Rho GTPase cycle. Rho cycles between an inactive, cytoplasmic, guanosine diphosphate (GDP) bound form and after geranylgeranylation is translocated to the plasma membrane and activated when it is bound to guanosine triphosphate (GTP). Inhibition of mevalonate synthesis by statins decreases geranylgeranyl pyrophosphate and prevents the geranylgeranylation of Rho and therefore its activation of Rho kinase (ROCK). ROCK mediates the downstream effects of Rho and has effect on endothelial cells, inflammatory cells, fibroblasts, cardiomyocytes, and vascular smooth muscle cells (SMC) that promote atherosclerosis and cardiac remodeling and may be responsible for the pleiotropic effects of statins. GG – geranylgeranyl, GDI – guanine nucleotide dissociation inhibitors, GEF – guanine nucleotide exchange factors, GAP – GTPase – activating proteins, PI3K - phosphatidylinositol 3-kinase, eNOS – endothelial nitric oxide synthase, CRD – Cysteine rich domain, RBD – Rho-binding domain