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 avasimibe can reduce atherogenesis independently of its cholesterol-lowering effect in ApoE*3-Leiden mice.


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.
Gaubius Laboratory, TNO-PG, Leiden, the Netherlands.
D J
DJ
Delsing
E H
EH
Offerman
W
W
van Duyvenvoorde
H
H
van Der Boom
E C
EC
de Wit
M J
MJ
Gijbels
A
A
van Der Laarse
J W
JW
Jukema
L M
LM
Havekes
H M
HM
Princen
D000081:Acetamides; D000085:Acetates / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use*; D000818:Animals; D000924:Anticholesteremic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D001021:Aortic Valve / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D053318:Apolipoprotein E3; D001057:Apolipoproteins E / Q000235:genetics*; D001161:Arteriosclerosis / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D001835:Body Weight / Q000187:drug effects; D002448:Cell Adhesion / Q000187:drug effects; D002460:Cell Line; D002784:Cholesterol / Q000097:blood* / Q000378:metabolism; D004036:Diet, Atherogenic; D004195:Disease Models, Animal; D004435:Eating / Q000187:drug effects; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D005260:Female; D006579:Heterozygote; D008074:Lipoproteins / Q000097:blood / Q000737:chemistry; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D051379:Mice; D008822:Mice, Transgenic; D002785:Sterol O-Acyltransferase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013449:Sulfonamides; D013451:Sulfonic Acids / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use*
D000081:Acetamides; D000085:Acetates; D000924:Anticholesteremic Agents; D053318:Apolipoprotein E3; D001057:Apolipoproteins E; D008074:Lipoproteins; D013449:Sulfonamides; D013451:Sulfonic Acids; C052720:apolipoprotein E3 (Leidein); C423185:avasimibe; D002784:Cholesterol; D002785:Sterol O-Acyltransferase