Effect of FR145237, a novel ACAT inhibitor, on atherogenesis in cholesterol-fed and WHHL rabbits. Evidence for a direct effect on the arterial wall

• Published in: Biochimica et biophysica acta Vol. 1259; no. 3; pp. 254 - 260
• Main Authors: Matsuo, Masahiko, Ito, Futoshi, Konto, Akiko, Aketa, Miho, Tomoi, Masaaki, Shimomura, Kyoichi
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 07.12.1995
• Subjects: Acyl-CoA:cholesterol acyltransferase; Animals; Aorta - chemistry; Aorta - drug effects; Arteriosclerosis - drug therapy; Arteriosclerosis - metabolism; Atherosclerosis; Benzofurans - pharmacology; Carrier Proteins; Cholesterol - analysis; Cholesterol - blood; Cholesterol, Dietary - administration & dosage; Diet, Atherogenic; Disease Models, Animal; Enzyme Inhibitors - pharmacology; Hypercholesterolemia; Hypercholesterolemia - drug therapy; Hypercholesterolemia - metabolism; Hyperlipidemias - drug therapy; Hyperlipidemias - genetics; Hyperlipidemias - metabolism; Lipoproteins, HDL; Lipoproteins, LDL - metabolism; Liver - chemistry; Liver - drug effects; Male; Molecular Structure; Phenylurea Compounds - pharmacology; Rabbit; Rabbits; Receptors, Lipoprotein - deficiency; RNA-Binding Proteins; Sterol O-Acyltransferase - antagonists & inhibitors; Rabbit; Acyl-CoA:cholesterol acyltransferase; Hypercholesterolemia; Atherosclerosis
• ISSN: 0005-2760; 0006-3002; 1879-145X
• DOI: 10.1016/0005-2760(95)00178-6

The hypocholesterolemic and antiatherosclerotic activities of FR145237, a novel acyl-CoA:cholesterol acyltransferase (ACAT) inhibitor, were evaluated in cholesterol-fed and Watanabe heritable hyperlipidemic (WHHL) rabbits. In the first experiment, rabbits were fed a high cholesterol (1% cholesterol) diet for 2 weeks and further fed a high cholesterol diet containing FR145237 for 8 weeks. FR145237 (0.1, 0.32 and 1.0 mg/kg) dose-dependently lowered the plasma total cholesterol levels by 80%, 96% and 97%, respectively, and reduced aortic atherosclerosis by 44%, 90% and 90%, respectively. To clarify a direct effect of FR145237 at the aortic wall, a second experiment was performed. Rabbits were fed a high-cholesterol diet for 8 weeks to establish aortic atherosclerosis and then fed a normal diet with or without FR145237 for 8 weeks. Cholesterol content in the aorta and the liver was significantly reduced in the FR145237 group (10 mg/kg) by 50% and 43%, respectively, though plasma total cholesterol level did not differ from that in the control group. In the WHHL rabbits, FR145237 (10 mg/kg) did not affect plasma cholesterol level but significantly reduced the atherosclerotic lesion in the coronary arteries by 61%. These results suggest that FR145237 potently lowers the plasma cholesterol level in hypercholesterolemia induced by dietary cholesterol but not that by LDL receptor deficiency, and that FR145237 has a direct antiatherosclerotic activity on the arterial wall independent of its hypocholesterolemic activity.