Acyl-CoA:Cholesterol Acyltransferase Inhibitor Avasimibe Reduces Atherosclerosis in Addition to Its Cholesterol-Lowering Effect in ApoE*3-Leiden Mice

Apr 3, 2001Circulation

Avasimibe lowers cholesterol and also reduces artery plaque in a mouse model of heart disease

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Abstract

A treatment with avasimibe resulted in a 92% reduction of atherosclerotic lesion area in ApoE*3-Leiden mice on a high-cholesterol diet.

Avasimibe lowered plasma cholesterol levels by 56%, primarily affecting VLDL and LDL types.
A separate low-cholesterol control group achieved plasma cholesterol comparable to the avasimibe group.
Compared to the low-cholesterol control, avasimibe treatment led to a 78% reduction in lesion area.
After adjusting for differences in cholesterol exposure, avasimibe still demonstrated a significant 73% reduction in lesion area.
Avasimibe treatment also reduced monocyte adherence to blood vessel linings and free cholesterol accumulation.

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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.

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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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