Lapaquistat acetate, a squalene synthase inhibitor, changes macrophage/lipid-rich coronary plaques of hypercholesterolaemic rabbits into fibrous lesions.
OBJECTIVE
Inhibition of squalene synthesis could transform unstable, macrophage/lipid-rich coronary plaques into stable, fibromuscular plaques. We have here treated WHHLMI rabbits, a model for coronary atherosclerosis and myocardial infarction, with a novel squalene synthase inhibitor, lapaquistat acetate (TAK-475).


METHODS
Young male WHHLMI rabbits were fed a diet supplemented with lapaquistat acetate (100 or 200 mg per kg body weight per day) for 32 weeks. Serum lipid levels were monitored every 4 weeks. After the treatment, lipoprotein lipid and coenzyme Q10 levels were assayed, and coronary atherosclerosis and xanthomas were examined histopathologically or immunohistochemically. From histopathological and immunohistochemical sections, the composition of the plaque was analysed quantitatively with computer-assisted image analysis. Xanthoma was evaluated grossly.


RESULTS
Lapaquistat acetate decreased plasma cholesterol and triglyceride levels, by lowering lipoproteins containing apoB100. Development of atherosclerosis and xanthomatosis was suppressed. Accumulation of oxidized lipoproteins, macrophages and extracellular lipid was decreased in coronary plaques of treated animals. Treatment with lapaquistat acetate increased collagen concentration and transformed coronary plaques into fibromuscular plaques. Lapaquistat acetate also suppressed the expression of matrix metalloproteinase-1 and plasminogen activator inhibitor-1 in the plaque and increased peripheral coenzyme Q10 levels. Increased coenzyme Q10 levels and decreased very low-density lipoprotein cholesterol levels were correlated with improvement of coronary plaque composition.


CONCLUSIONS
Inhibition of squalene synthase by lapaquistat acetate delayed progression of coronary atherosclerosis and changed coronary atheromatous plaques from unstable, macrophage/lipid accumulation-rich, lesions to stable fibromuscular lesions.
Shiomi
M
M
Institute for Experimental Animals, Kobe University School of Medicine, Kobe, Japan. ieakusm@med.kobe-u.ac.jp
Yamada
S
S
Amano
Y
Y
Nishimoto
T
T
Ito
T
T
D000818:Animals; D053299:Apolipoprotein B-100 / Q000097:blood; D002784:Cholesterol / Q000097:blood; D003094:Collagen / Q000378:metabolism; D003324:Coronary Artery Disease / Q000201:enzymology / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D004195:Disease Models, Animal; D018450:Disease Progression; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000097:blood / Q000494:pharmacology*; D013186:Farnesyl-Diphosphate Farnesyltransferase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006937:Hypercholesterolemia / Q000150:complications / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D000960:Hypolipidemic Agents / Q000097:blood / Q000494:pharmacology*; D007090:Image Interpretation, Computer-Assisted; D007150:Immunohistochemistry; D050356:Lipid Metabolism / Q000187:drug effects; D008077:Lipoproteins, LDL / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects* / Q000473:pathology; D008297:Male; D020781:Matrix Metalloproteinase 1 / Q000378:metabolism; D010077:Oxazepines / Q000097:blood / Q000494:pharmacology*; D010880:Piperidines / Q000097:blood / Q000494:pharmacology*; D017395:Plasminogen Activator Inhibitor 1 / Q000378:metabolism; D011817:Rabbits; D014280:Triglycerides / Q000097:blood; D014451:Ubiquinone / Q000031:analogs & derivatives / Q000378:metabolism; D014973:Xanthomatosis / Q000201:enzymology / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*
C466644:1-((1-(3-acetoxy-2,2-dimethylpropyl)-7-chloro-5-(2,3-dimethoxyphenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-yl)acetyl)piperidine-4-acetic acid; D053299:Apolipoprotein B-100; D004791:Enzyme Inhibitors; D000960:Hypolipidemic Agents; D008077:Lipoproteins, LDL; D010077:Oxazepines; D010880:Piperidines; D017395:Plasminogen Activator Inhibitor 1; D014280:Triglycerides; C099252:oxidized low density lipoprotein; D014451:Ubiquinone; D003094:Collagen; D002784:Cholesterol; D013186:Farnesyl-Diphosphate Farnesyltransferase; D020781:Matrix Metalloproteinase 1; C024989:coenzyme Q10