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

Article

关键词: LEIDEN TRANSGENIC MICE;    APOLIPOPROTEIN-B;    ACAT INHIBITORS;    ANTIATHEROSCLEROTIC ACTIVITY;    TRANSFERASE ACAT;    MINIATURE PIGS;    COENZYME-A;    IN-VIVO;    DECREASES;    SECRETION;   

DOI  :  10.1161/01.CIR.103.13.1778

来源: SCIE

【 摘 要 】

Background-The present study investigated whether the ACAT inhibitor avasimibe can reduce atherogenesis independently of its cholesterol-lowering effect 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 mixed into the diet. The HC diet resulted in a plasma cholesterol concentration of 18.7 +/-2.6 mmol/L. Addition of avasimibe lowered plasma cholesterol by 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 avasimibe group (10.3 +/-1.3 mmol/L) by lowering the amount of dietary cholesterol. After 22 weeks of intervention, atherosclerosis in the aortic root area was quantified. Treatment with avasimibe resulted in a 92% reduction of lesion area compared with the HC control group. Compared with the LC control, avasimibe reduced lesion area by 78%. After correction for the slight difference in cholesterol exposure between the LC control and avasimibe groups, the effect of avasimibe on lesion area (73% reduction) remained highly significant. In addition, monocyte adherence to the endothelium, free cholesterol accumulation, and lesion severity were reduced by avasimibe treatment. Conclusions-Treatment with avasimibe potently lowered plasma cholesterol levels in ApoE*3-Leiden mice and considerably reduced atherosclerotic lesion area in addition to its cholesterol-lowering effect. Because monocyte adherence to the endothelium and lesion severity were also reduced by avasimibe, treatment with avasimibe may result in higher plaque stability and therefore a reduced risk of plaque rupture.

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