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

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Author: Delsing, D.J.M. · Offerman, E.H. · Duyvenvoorde, W. van · Boom, H. van der · Wit, E.C.M. de · Gijbels, M.J.J. · Laarse, A. van der · Jukema, J.W. · Havekes, L.M. · Princen, H.M.G.
Type:article
Date:2001
Institution: Gaubius Instituut TNO
Source:Circulation, 13, 103, 1778-1786
Identifier: 236025
Keywords: Biology · Acetates · Animals · Anticholesteremic Agents · Aortic Valve · Apolipoprotein E3 · Apolipoproteins E · Arteriosclerosis · Body Weight · Cell Adhesion · Cell Line · Cholesterol · Diet, Atherogenic · Disease Models, Animal · Eating · Endothelium, Vascular · Female · Heterozygote · Lipoproteins · Macrophages · Mice · Mice, Transgenic · Sterol O-Acyltransferase · Sulfonic Acids

Abstract

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 (HC) 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±1.4 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. Chemicals/CAS: Acetates; Anticholesteremic Agents; apolipoprotein E3 (Leidein); Apolipoprotein E3; Apolipoproteins E; avasimibe, 166518-60-1; Cholesterol, 57-88-5; Lipoproteins; Sterol O-Acyltransferase, EC 2.3.1.26; Sulfonic Acids