Rho GTPases, statins, and nitric oxide

Abstract

The lipid-lowering drugs, 3-hydroxy-3-methylgulutaryl-coenzyme A (HMG-CoA) reductase inhibitors or statins, are used in the prevention and treatment of cardiovascular diseases. Recent experimental and clinical studies suggest that statins may exert vascular protective effects beyond cholesterol reduction. For example, statins improve endothelial function by cholesterol-dependent and -independent mechanisms. The cholesterol-independent or "pleiotropic" effects of statins include the upregulation and activation of endothelial NO synthase (eNOS). Because statins inhibit an early step in the cholesterol biosynthetic pathway, they also inhibit the synthesis of isoprenoids such as farnesylpyrophosphate and geranylgeranylpyrophosphate, which are important posttranslational lipid attachments for intracellular signaling molecules such as the Rho GTPases. Indeed, decrease in Rho GTPase responses as a consequence of statin treatment increases the production and bioavailability of endothelium-derived NO. The mechanism involves, in part, Rho/Rho-kinase (ROCK)-mediated changes in the actin cytoskeleton, which leads to decreases in eNOS mRNA stability. The regulation of eNOS by Rho GTPases, therefore, may be an important mechanism underlying the cardiovascular protective effect of statins.

Figure 1

Cholesterol biosynthesis pathway and the effects of statins. Inhibition of HMG-CoA reductase by statins decreases isoprenoid intermediates such as farnesyl-PP and geranylgeranyl-PP, which leads to an inhibition of isoprenylation of small GTPases such as Ras, Rho, Rab, and Rap. Among the Rho GTPases are RhoA, Rac1, and Cdc42. CoA indicates coenzyme A; PP, pyrophosphate.

Figure 2

Regulation of eNOS expression and activity by statins, Rho, ROCK, and actin cytoskeleton. Statins suppress translocation of Rho by inhibiting isoprenylation of Rho. Active forms of Rho and ROCK decrease eNOS mRNA stability and eNOS phosphorylation, resulting in downregulation of eNOS expression and decrease in eNOS activity. Inhibition of Rho and ROCK activity by statins may chronically upregulate of eNOS expression and acutely stimulate eNOS activity.