Acyl-CoA: Cholesterol acyltransferase inhibitor avasimibe reduces atherosclerosis in addition to its cholesterol-lowering effect in ApoE*3-Leiden mice

Background-The present study investigated whether the ACAT inhibitor avasim ibe can reduce atherogenesis independently of its cholesterol-lowering effe ct in ApoE*3-Leiden mice. Methods and Results-Two groups of 15 female ApoE*3-Leiden mice were put on a high-cholesterol (PIC) diet; 1 group received 0.01% (wt/wt) avasimibe mix ed into the diet. The HC diet resulted in a plasma cholesterol concentratio n of 18.7 +/-2.6 mmol/L. Addition of avasimibe lowered plasma cholesterol b y 56% to 8.1 +/-1.2 mmol/L, caused mainly by a reduction of and composition change in VLDL and LDL. In a separate low-cholesterol (LC) control group, plasma cholesterol was titrated to a level comparable to that of the avasim ibe group (10.3 +/-1.3 mmol/L) by lowering the amount of dietary cholestero l. After 22 weeks of intervention, atherosclerosis in the aortic root area was quantified. Treatment with avasimibe resulted in a 92% reduction of les ion area compared with the HC control group. Compared with the LC control, avasimibe reduced lesion area by 78%. After correction for the slight diffe rence in cholesterol exposure between the LC control and avasimibe groups, the effect of avasimibe on lesion area (73% reduction) remained highly sign ificant. In addition, monocyte adherence to the endothelium, free cholester ol accumulation, and lesion severity were reduced by avasimibe treatment. Conclusions-Treatment with avasimibe potently lowered plasma cholesterol le vels in ApoE*3-Leiden mice and considerably reduced atherosclerotic lesion area in addition to its cholesterol-lowering effect. Because monocyte adher ence to the endothelium and lesion severity were also reduced by avasimibe, treatment with avasimibe may result in higher plaque stability and therefo re a reduced risk of plaque rupture.