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

Abstract

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 cholestrol 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.

• Authors: M Matsuo, F Ito, A Konto, M Aketa, M Tomoi, K Shimomura
• Journal: Biochimica et biophysica acta (Biochim Biophys Acta) Vol. 1259 Issue 3 Pg. 254-60 (Dec 07 1995) ISSN: 0006-3002 [Print] Netherlands
• PMID: 8541332 (Publication Type: Journal Article)

Chemical References

• Benzofurans
• Carrier Proteins
• Cholesterol, Dietary
• Enzyme Inhibitors
• FR 145237
• Lipoproteins, HDL
• Lipoproteins, LDL
• Phenylurea Compounds
• RNA-Binding Proteins
• Receptors, Lipoprotein
• high density lipoprotein receptors
• high density lipoprotein binding protein
• Cholesterol
• Sterol O-Acyltransferase

Topics

• Animals
• Aorta (chemistry, drug effects)
• Arteriosclerosis (drug therapy, metabolism)
• Benzofurans (pharmacology)
• Carrier Proteins
• Cholesterol (analysis, blood)
• Cholesterol, Dietary (administration & dosage)
• Diet, Atherogenic
• Disease Models, Animal
• Enzyme Inhibitors (pharmacology)
• Hypercholesterolemia (drug therapy, metabolism)
• Hyperlipidemias (drug therapy, genetics, metabolism)
• Lipoproteins, HDL
• Lipoproteins, LDL (metabolism)
• Liver (chemistry, drug effects)
• Male
• Molecular Structure
• Phenylurea Compounds (pharmacology)
• RNA-Binding Proteins
• Rabbits
• Receptors, Lipoprotein (deficiency)
• Sterol O-Acyltransferase (antagonists & inhibitors)