ENDOTHELIAL DYSFUNCTION IN ATHEROSCLEROSI S - PROTECTIVE ROLE OF STATINS

Atherosclerosis is a chronic disease of the vascular wall characterize d by macrophage accumulation, vascular smooth muscle cell proliferatio n and extracellular matrix intimal formation. A deficient :function in the L-arginine-nitric oxide (NO)-cGMP pathway or an excess of endothe lin-1 (ET-1) have been related with the endothelial dysfunction associ ated to arteriosclerosis. This derangement is one of the first steps i n the atherogenetic process. inhibitors of 3-hydroxi-3-methyl-glutaryl CoA reductase (statins) have been succesfully employed in the treatme nt of dyslipidemia and atherosclerosis. These drugs reduce cholesterol levels by inhibiting mevalonate synthesis, a precursor step in the st erol biosynthetic pathway. Recent clinical studies have reported that, aside from their cholesterol lowering action, statins may ameliorate endothelial function by additional mechanisms. Based on these observat ions, we have studied the potential effect of statins on the expressio n of the endothelial vasoactive factors, ET-1 and NO in bovine aortic endothelial cells (BAEC). Our results show that Atorvastatin and Simva statin significantly reduce the synthesis oi ET-1 and the expression o f the pre-proET-1 mRNA. This effect is also evident in the presence of proatherogenic concentrations of oxidized low density lipoproteins (o xLDLs). Although no significant modification of endothelial NO synthas e levels was observed in the presence of these drugs alone, they clear ly reduced oxLDL-mediated inhibition in BAEC. Thus, statins may contri bute to the regulation of vascular tone by modifying the expression of endothelial vasoactive factors.