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(Circulation. 2004;109:II-34 – II-41.)
© 2004 American Heart Association, Inc.

Vascular Effects of Statins

Effects of HMG-CoA Reductase Inhibitors on Endothelial Function

Role of Microdomains and Oxidative Stress

R. Preston Mason, PhD; Mary F. Walter, PhD; Robert F. Jacob, PhD

From the Cardiovascular Division, Department of Medicine (R.P.M.), Brigham and Women’s Hospital, Harvard Medical School, Boston, Mass; and the Cardiovascular Research Group (R.P.M., M.F.W., R.F.J.), Elucida Research LLC, Beverly, Mass.

Correspondence to R. Preston Mason, PhD, 100 Cummings Center, Suite 135L, Beverly, MA 01915. E-mail rpmason{at}elucidaresearch.com

Abstract

Certain pleiotropic activities reported for 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) are related to reductions in cellular cholesterol biosynthesis and isoprenoid levels. In endothelial cells, these metabolic changes contribute to favorable effects on nitric oxide (NO) bioavailability. Given the essential role of NO in preserving vascular structure and function, this effect of statins is of considerable therapeutic importance. Statins have been demonstrated to restore endothelial NO production by several mechanisms, including upregulating endothelial NO synthase (eNOS) protein expression and blocking formation of reactive oxygen species. In this article, we will discuss additional ways in which statins restore endothelial NO production and improve endothelial function. (1) Statins modulate membrane microdomain formation, resulting in reduced expression of proteins that specifically inhibit eNOS activation. (2) Statins reduce sterol biosynthesis, thus interfering with the formation of pathologic microdomains, including cholesterol crystalline structures. This observation has important implications for plaque stabilization, as these microdomains contribute to cholesterol crystal formation and endothelial apoptosis. Finally, (3) statins improve endothelial function by interfering with oxidative stress pathways through both enzymatic and nonenzymatic mechanisms. The relationships between membrane microdomains, cholesterol biosynthesis, and endothelial function will be discussed.

Key Words: atherosclerosis • endothelial function • microdomain • nitric oxide • statins

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