Effects of statins on vascular wall: vasomotor function, inflammation, andplaque stability

Clinical trials of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductas e inhibitors or statin therapy demonstrate an improvement in cardiovascular end points and coronary stenosis. However, an improvement in cardiovascula r end points and coronary stenosis is incompletely explained by the baselin e or treated LDL cholesterol level. The beneficial effects of statins on cl inical events may involve nonlipid mechanisms that modify endothelial funct ion, smooth muscle cells, and monocyte-macrophage: vasomotor function, infl ammatory responses, and plaque stability. Augmented bioactivity of NO by st atin therapy either indirectly by its effect on lipoprotein Levels and prot ection of LDL from oxidation, or directly by effects on NO synthesis and re lease, might account for enhancement of endothelium-dependent vasodilation. Recent experimental and animal studies have demonstrated that statins dose -dependently decrease smooth muscle cells migration and proliferation, inde pendently of their ability to reduce plasma cholesterol. Moreover, statins are able to reduce the in vitro cholesterol accumulation in macrophages and expression of matrix metalloproteinase, resulting in plaque stability. The se effects of statins were completely prevented by the addition of mevalona te and partially by all-trails farnesol and all-trans geranylgeraniol, conf irming the specific role of isoprenoid metabolites, probably through prenyl ated proteins, in regulating these cellular events. Statins have been shown to prevent the activation of monocytes into macrophages, inhibit the produ ction of pro-inflammatory cytokines, C-reactive protein, and cellular adhes ion molecules. Statins decrease the adhesion of monocyte to endothelial cel ls. Accordingly, statins exert their cardiovascular benefits through a dire ct antiatherogenic properties in the arterial wall, beyond their effects on plasma lipids. (C) 2000 Elsevier Science B.V. All rights reserved.