The statin group of drugs has revolutionized the treatment of coronary atherosclerosis since their introduction nearly two decades ago. By competitively inhibiting the rate-limiting enzyme in cholesterol biosynthesis, 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase, intrahep-atic cholesterol is reduced, thereby leading to an increase in low-density lipoprotein (LDL) receptor expression and consequent enhanced endocytosis of plasma LDL cholesterol. Older therapies for hyperlipidemia, although capable of lowering cholesterol, did not have a significant impact on clinical outcomes in cardiovascular disease. The beneficial effects of statin therapy correlate poorly with reductions in serum cholesterol. In addition, improvements in clinical outcomes have been noted well before any changes in lipid levels. These observations led to the hypothesis that statins have vasculoprotective effects independent of cholesterol lowering . In 1996, the first such mechanism to be elucidated was the inhibition of vascular smooth muscle cell (VSMC) proliferation, followed in 1998 by the discovery that statins increase the expression and activity of endothe-lial nitric oxide synthase (eNOS) in vascular endothelial cells (EC). Since that time a host of other, so-called pleiotropic actions have been described, making this phar-macologic class of agents the target of intensive research efforts in a broad variety of disease states.
The microvascular endothelium plays a critical role in the regulation of regional blood flow, and endothelial dysfunction is central to many cardiovascular diseases. Several beneficial effects on the endothelium are induced by statins that maintain adequate tissue perfusion, such as enhanced eNOS and fibrinolytic activity. The microvascular endothe-lium is a major target, as well as a source of oxidant and immune/inflammatory-induced injury. HMG-CoA reductase inhibitors possess potent antioxidant and anti-inflammatory properties that may prove beneficial in diverse pathologic processes. Capillary angiogenesis is crucial to increasing blood flow in chronically ischemic tissues, and statin effects on the endothelium have been shown to alter this process as well. Thus, the vasculoprotective effects of statins serve to maintain the integrity of the microvasculature, particularly its endothelial lining, allowing it to perform its central function of controlling local blood flow and exchange of nutrients with the interstitial space, while preventing edema formation and the efflux of inflammatory cells.
This review will begin with a discussion of the molecular mechanisms mediating the pleiotropic actions of statins. Then, those effects with particular relevance to the microcirculation will be summarized, followed by an overview of the potential clinical applications.
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