Cholesterol modulates vascular reactivity to endothelin-1 by stimulating apro-inflammatory pathway

Hypercholesterolemia (HC) is associated with coronary endothelial dysfuncti on and increased circulating levels of endothelin-l. We show that pre-treat ment of intact rat aortic rings with cholesterol synergistically enhances t he vasoconstriction induced by endothelin-l suggesting that elevated levels of cholesterol may predispose to hypertension by modulating the vascular r eactivity to endogenous vasoconstrictors. Moreover, we report that SB202190 , a selective inhibitor of p38 MAPK, and PD98059 an inhibitor of MEK1/2 are able to abolish the vasoactive properties of cholesterol. MK-886, an inhib itor of 5-lipoxygenase is inefficient at blocking the vasoactive properties of cholesterol whereas NS-398, a selective inhibitor of cyclooxygenase-a ( COX-2) completely abolishes cholesterol-induced vasoconstriction. In intact rat aortae, cholesterol stimulates prostaglandin E-2 and prostaglandin F-2 alpha production, an effect that can be completely prevented by inhibiting p38 MAPK, or COX-2. In vitro, cholesterol appears to stimulate a similar p ro-inflammatory pathway in human cerebrovascular smooth muscle cells. Disru ption of the MAPK/COX-2 pathway may represent a valuable therapy to block t he hypertension associated with HC, as well as the development of atheroscl erosis. (C) 2000 Academic Press.