INHIBITION OF ACYL-COA CHOLESTEROL O-ACYLTRANSFERASE REDUCES THE CHOLESTERYL ESTER ENRICHMENT OF ATHEROSCLEROTIC LESIONS IN THE YUCATAN MICROPIG

Atherosclerotic lesion development may be altered indirectly by regula ting plasma cholesterol or directly by inhibition of acyl-CoA choleste rol O-acyltransferase (ACAT) within cells of the artery. Yucatan micro pigs were meal-fed a 2% cholesterol, 8% peanut oil, 8% coconut oil pur ified diet for 1 month prior to administration of the potent, bioavail able ACAT inhibitor CI-976, and induction of atherosclerotic lesions b y chronic endothelial damage. After 84-108 days of therapy, CI-976 dec reased mean plasma VLDL-cholesterol 85-91% and cumulative VLDL-exposur e (area under VLDL-time curve) by 65%. However, overall plasma total, LDL and HDL cholesterol and triglyreride levels were unchanged. CI-976 decreased liver cholesteryl ester (CE) content 65% without significan tly affecting adrenal CE content. The CE content of the injured left f emoral, left iliac and abdominal aorta and uninjured right femoral and iliac arteries and thoracic aorta was reduced 62-78% by CI-976. Syste mic plasma CI-976 levels measured 24 h post-dose ranged from 2.26 to 4 .05 mug/ml and significantly correlated with the reduction in both VLD L and vessel CE content. Thus, we conclude that inhibition of ACAT can blunt the cholesteryl ester enrichment of developing atherosclerotic lesions by preventing reesterification and storage of lipoprotein chol esterol within vascular cells and by reducing the plasma level and del ivery to the arterial wall of such atherogenic lipoproteins as VLDL.