Direct effect of an acyl-CoA : cholesterol acyltransferase inhibitor, F-1394, on atherosclerosis in apolipoprotein E and low density lipoprotein receptor double knockout mice

1 The acyl-CoA:cholesterol acyltransferase (ACAT) enzyme is thought to be r esponsible for foam cell formation and the subsequent progression of athero sclerosis. The apolipoprotein E and low density lipoprotein receptor double knockout (apoE/LDLr-DKO) mouse is an animal model that develops severe hyp erlipidaemia and atherosclerosis. 2 Here we have examined the effect of oral administration of an ACAT inhibi tor, F-1394, on atherosclerosis in apoE/LDLr-DKO mice fed a regular chow di et. 3 In en face analysis, a dose of 10, 30, or 100 mg kg(-1) day(-1) F-1394 fo r 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 affecti ng serum cholesterol level in these mice. At the highest dose 100 mg kg(-1) day(-1) of F-1394, the reduction was statistically significant. 4 For quantitative analysis of the cellular and non-cellular components com prising the lesions at the aortic sinus, the effects of an oral dose of 100 mg kg(-1) day(-1) F-1394 for 15 weeks were studied. There was a significan t 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 signific ant). However, the areas containing macrophages, smooth muscle cells, and c ollagen were not affected by F-1394. 5 In vitro, F-1394 attenuated foam cell formation in mouse peritoneal macro phages. 6 These results indicate that ACAT may be primarily responsible for lipid a ccumulation in atherosclerotic lesions, and that its inhibition diminishes the lipid deposition via a direct effect on macrophages in the arterial wal l.