Direct effect of an acyl-CoA:cholesterol acyltransferase inhibitor, F-1394, on atherosclerosis in apolipoprotein E and low density lipoprotein receptor double knockout mice
| Autor: | Koji Fujinami, Katsumi Aragane, Tsuyoshi Chiwata, Nobuhiro Yamada, Shun Ishibashi, Jun Kusunoki, Kazuhiro Kojima |
|---|---|
| Rok vydání: | 2001 |
| Předmět: |
Pharmacology
Apolipoprotein E medicine.medical_specialty Cholesterol Sterol O-acyltransferase Arteriosclerosis Biology medicine.disease chemistry.chemical_compound Endocrinology chemistry Internal medicine LDL receptor Knockout mouse medicine Oil Red O lipids (amino acids peptides and proteins) Foam cell |
| Zdroj: | British Journal of Pharmacology. 133:1005-1012 |
| ISSN: | 0007-1188 |
| Popis: | 1 The acyl-CoA:cholesterol acyltransferase (ACAT) enzyme is thought to be responsible for foam cell formation and the subsequent progression of atherosclerosis. The apolipoprotein E and low density lipoprotein receptor double knockout (apoE/LDLr-DKO) mouse is an animal model that develops severe hyperlipidaemia and atherosclerosis. 2 Here we have examined the eAect of oral administration of an ACAT inhibitor, F-1394, on atherosclerosis in apoE/LDLr-DKO mice fed a regular chow diet. 3 In en face analysis, a dose of 10, 30, or 100 mg kg 71 day 71 F-1394 for 10 weeks reduced the extent of lesions visible in the aorta by 24, 28 and 38%, respectively, as detected by staining with oil red O, without aAecting serum cholesterol level in these mice. At the highest dose 100 mg kg 71 day 71 of F-1394, the reduction was statistically significant. 4 For quantitative analysis of the cellular and non-cellular components comprising the lesions at the aortic sinus, the eAects of an oral dose of 100 mg kg 71 day 71 F-1394 for 15 weeks were studied. There was a significant reduction (31.9%) in the oil-red O-stained area in cross-sections of the aortic sinus. In addition, the neointimal area, as well as levels of ACAT-1 protein tended to be decreased (15.2 and 25.8%, respectively, not significant). However, the areas containing macrophages, smooth muscle cells, and collagen were not aAected by F-1394. 5 In vitro, F-1394 attenuated foam cell formation in mouse peritoneal macrophages. 6 These results indicate that ACAT may be primarily responsible for lipid accumulation in atherosclerotic lesions, and that its inhibition diminishes the lipid deposition via a direct eAect on macrophages in the arterial wall. British Journal of Pharmacology (2001) 133, 1005‐1012 |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Plný text