Pleiotropic effects of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors

The 3-hydroxy-3-methylglutaryl coenzyme. A reductase inhibitors or statins are potent inhibitors of cholesterol biosynthesis. Several large clinical t rials have demonstrated the beneficial effects of statins in the primary an d secondary prevention of coronary heart disease. However, the overall clin ical benefits observed with statin therapy appear to be greater than what m ight be expected from changes in lipid profile alone, suggesting that the b eneficial effects of statins may extend beyond their effects on serum chole sterol levels. Indeed, recent experimental and clinical evidence indicates that some of the cholesterol-independent or "pleiotropic" effects of statin s involve improving or restoring endothelial function, enhancing the stabil ity of atherosclerotic plaques, and decreasing oxidative stress and vascula r inflammation. Many of these pleiotropic effects of statins are mediated b y their ability to block the synthesis of important isoprenoid intermediate s, which serve as lipid attachments for a variety of intracellular signalin g molecules. In particular, the inhibition of small GTP-binding proteins, R ho, Ras, and Rac, whose proper membrane localization and function are depen dent on isoprenylation, may play an important role in mediating the direct cellular effects of statins on the vascular wall.