Pleiotropic effects of HMG-CoA reductase inhibitors

HMG-CoA reductase, in addition to being the rate-limiting enzyme in the cholesterol biosynthetic pathway, is involved in the regulation of receptors for low-density lipoprotein (LDL)-cholesterol. Clinical studies in men and women demonstrate that inhibitors of HMG-CoA reductase (statins), by reducing plasma cholesterol, may limit the development of atherosclerosis and reduce the risk of mortality and ischemic events. Preclinical evidence suggests that under controlled conditions of plasma cholesterol lowering, statins may have ancillary properties or pleiotropic effects, which may directly limit atherosclerosis progression. In this review, pleiotropic effects have been defined as 'ancillary properties of statins, which result in hepatic and/or vascular changes that may or may not be a consequence of inhibition of HMG-CoA reductase.' Beyond the LDL lowering activity of statins, improvements have been noted in endothelial dysfunction through direct stimulation of expression of such vasodilators as nitric oxide and/or reduction in vasoconstrictors. Factors associated with atherogenesis, such as monocyte adhesion to endothelial cells, macrophage production of proinflammatory molecules and matrix metalloproteases, smooth muscle cell proliferation and migration and macrophage-induced oxidation of LDL particles have also been reduced by various statins. It is unclear whether the observed pleiotropic effects are independent of LDL-cholesterol lowering or inhibition of HMG-CoA reductase, and whether they are clinically relevant; however, one can conclude that the pleiotropic effects appear to be a class effect of statins and can be attenuated by addition of the post-reductase product, mevalonate.