INHIBITION OF CHOLESTEROL ESTERIFICATION IN MACROPHAGES AND VASCULAR SMOOTH-MUSCLE FOAM CELLS - EVALUATION OF E5324, AN ACYL-COA CHOLESTEROL ACYLTRANSFERASE INHIBITOR

Cholesteryl esters (CE) comprise the principal lipid class that accumu lates within macrophages and smooth muscle cells of the atheroscleroti c lesion. Acyl-CoA cholesterol acyl transferase (ACAT) is the major en zyme responsible for esterification of intracellular cholesterol. We e valuated the ability of E5324 l-1H-imidazol-1-yl)propoxyl-6-methyl-phe nyl]urea), a novel, orally absorbable ACAT inhibitor, to inhibit ester ification of fatty acids to cholesterol and CE accumulation in macroph ages and in smooth muscle cells. E5324 significantly inhibited cholest erol esterification in rat aortic smooth muscle cells and in macrophag es. in addition, E5324 reduced the cellular mass of CE, the significan t measure of the efficacy of drugs designed to modulate cholesterol me tabolism. E5324 treatment of macrophages exposed to acetylated low-den sity lipoprotein reduced CE mass by 97%, and treatment of lipid-loaded smooth muscle cells reduced CE mass by 29%. Although free cholesterol increased approximately twofold, this free cholesterol would presumab ly be accessible to the membrane for efflux in vivo (reverse cholester ol transport). These results demonstrate that E5324 can inhibit choles terol esterification and CE mass in atherosclerotic foam cells, derive d from either macrophages or arterial smooth muscle cells.