Cracking down on caveolin: role of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors in modulating edothelial cell nitric oxide production

One of the most effective approaches in the treatment of atherosclerosis has been the use of 3-hydroxy-3-methylglutaryl–coenzyme A reductase inhibitors (statins) to treat hypercholesterolemia. During the past decade, numerous studies involving >20 000 individuals have shown that these drugs dramatically reduce cardiovascular death, myocardial infarction, unstable angina, and stroke. Statin therapy prevents events in individuals with established cardiovascular disease and is also effective in primary prevention.1 A major mechanism by which lipid lowering is thought to improve outcome is by preventing the development of new atherosclerotic lesions and by depleting lipids from established plaques (ie, plaque stabilization).2 3 A striking finding is that statins seem to decrease clinical events within a few months of the onset of therapy.4 This suggests that they may have beneficial effects beyond those of plaque stabilization and lesion prevention. One such beneficial effect might be the restoration of nitric oxide production by the endothelium. Endothelium-derived nitric oxide, previously known as the endothelium-derived relaxing factor, modulates vasodilatation and prevents platelet adhesion, the expression of adhesion molecules, and smooth muscle cell proliferation.5 Nitric oxide has also been shown to have antioxidant effects by enhancing the expression of superoxide dismutase,6 preventing lipid-chain reactions,7 and reacting with the superoxide anion.5 Thus, nitric oxide seems to play a major role as an endogenous protective factor against atherosclerosis. Indeed, virtually every atherosclerosis risk factor is associated with decreased endothelial cell nitric oxide production, and it is likely that this loss of nitric oxide is a major reason why these conditions predispose to vascular lesion development. …