Acyl-CoA:Cholesterol acyltransferase inhibitor avasimibe reduces atherosclerosis in addition to its cholesterol-lowering effect in ApoE*3-leiden mice
article
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
Topics
AcetatesAnimalsAnticholesteremic AgentsAortic ValveApolipoprotein E3Apolipoproteins EArteriosclerosisBody WeightCell AdhesionCell LineCholesterolDiet, AtherogenicDisease Models, AnimalEatingEndothelium, VascularFemaleHeterozygoteLipoproteinsMacrophagesMiceMice, TransgenicSterol O-AcyltransferaseSulfonic Acids
TNO Identifier
236025
ISSN
00097322
Source
Circulation, 103(13), pp. 1778-1786.
Pages
1778-1786
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