F-1394, an ACAT Inhibitor, Inhibits Neointimal Thickening and Macrophage Accumulation after Balloon Injury in the Cholesterol-Fed Rabbit

Acyl-CoA:cholesterol acyltransferase (ACAT) catalyzes the accumulation of lipid droplets in macrophages, leading to the formation of foam cells, which are responsible for the initiation and progression of atherosclerosis. F-1394 is a potent, selective and competitive inhibitor of ACAT. F-1394 inhibited the incorporation of 14C-oleic acid into cholesteryl oleate in phorbol ester-treated THP-1 cells. When THP-1 cells were cultured with 14C-cholesterol-labeled s-VLDL obtained from rabbits fed a high-cholesterol diet, a large quantity of 14C-cholesterol ester was observed. The amount of radiolabeled cholesteryl ester was significantly reduced by treatment with F-1394 in a dose-dependent manner. In rabbits with intimai thickening in the carotid artery induced by both balloon-catheter injury and a high-cholesterol diet, F-1394 significantly reduced the intimai thickening and RAM-11-positive area in the lesions without changing serum cholesterol levels. These results suggest that foam cells greatly contribute to the progression of intimai thickening in the arterial wall injured by balloon-catheter, and that F-1394 prevents the thickening by reducing of the number of foam cells in the lesion. Therefore, F-1394 may have a potential beneficial effect for the therapy of atherosclerotic patients.