Pleiotropic effects of statins and related pharmacological experimental approaches.

Abstract

Statins, the most widely prescribed cholesterol-lowering drugs, are considered to be first-line therapeutics for the prevention of coronary heart disease and atherosclerosis. Statins act by inhibiting the enzyme 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase, the rate-limiting enzyme in endogenous cholesterol biosynthesis, which catalyzes the reduction of HMG-CoA to mevalonic acid. Inhibition of this enzyme has proven to be effective for lowering plasma total cholesterol, low-density lipoprotein-cholesterol, and triglyceride levels in humans and can therefore be useful to treat atherosclerotic and dyslipidemic disorders. However, the clinical benefits of statins appear to extend beyond their lipid-lowering effects. Besides reducing cholesterol biosynthesis, inhibition of mevalonate by statins also leads to a reduction in the synthesis of important intermediates, such as the isoprenoids farnesyl pyrophosphate and geranylgeranyl pyrophosphate. These intermediates are involved in the posttranslational prenylation of several proteins (e.g., Ras, Rho, Rac) that modulate a variety of cellular processes including cellular signaling, differentiation, and proliferation. Given the central role of these isoprenylated proteins in endothelial function, atherosclerotic plaque stability, platelet activity, coagulation, oxidation, and inflammatory and immunologic responses, it could be anticipated that these compounds may exert multiple beneficial effects in a broad spectrum of disorders including cardiovascular disease, osteoporosis, Alzheimer's disease and related vascular dementia, viral and bacterial infection, etc. This article summarizes these cholesterol-lowering-independent effects of statins, termed "pleiotropic effects," and the underlying mechanisms, as well as the preclinical experimental approaches that would be useful to evaluate the effects of statins.