Risk factors for cardiovascular disease, such as cigarette smoking, hypertension, and elevated serum lipid levels impair endothelial function and lead to the development of atherosclerosis. Recent studies suggest that 3-hydroxy-3-methylglutaryl- CoA (HMG-CoA) reductase inhibitors or statins reduce cardiovascular events, in part, by improving endothelial function. Statins reduce plasma cholesterol levels, thereby decreasing the uptake of modified lipoproteins by endothelial cells (ECs). There is increasing evidence, however, that statins may also exert effects beyond cholesterol lowering. Many of these cholesterol-independent or “pleiotropic” vascular effects of statins appear to involve restoring or improving endothelial function by increasing the bioavailability of nitric oxide (NO), promoting re-endothelization, reducing oxidative stress, inhibiting inflammatory responses, and increasing fibrinolysis. Thus, the endothelium-dependent effects of statinsmay contribute to many of the beneficial effects of statin therapy in cardiovascular disease.

STATINS AND ENDOTHELIAL FUNCTION

Statins inhibit an early rate-limiting step in cholesterol biosynthesis (Figure 179.1). This leads to increased hepatic low density lipoprotein (LDL) receptors and enhanced uptake of cholesterol by the liver. Indeed, therapeutic doses of statins potently reduce serum cholesterol levels in humans, and several large clinical trials have demonstrated that inhibition of HMG-CoA reductase by statins markedly decreases the incidence of cardiovascular events in hypercholesterolemic individuals (1,2). Because of the strong association between elevated serum cholesterol levels and coronary atherosclerotic disease, the reduction of serum cholesterol levels by statins has been proposed to be the predominant mechanism underlying the beneficial effects of these drugs. Indeed, acute plasma LDL aphaeresis improves endothelium-dependent vasodilatation (3), suggesting that statins could restore endothelial function, in part, by lowering serum cholesterol levels.