Document Detail


Lapaquistat acetate, a squalene synthase inhibitor, changes macrophage/lipid-rich coronary plaques of hypercholesterolaemic rabbits into fibrous lesions.
MedLine Citation:
PMID:  18587443     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
BACKGROUND AND PURPOSE: 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).
EXPERIMENTAL APPROACH: 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.
KEY 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.
CONCLUSION AND IMPLICATIONS: 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.
Authors:
M Shiomi; S Yamada; Y Amano; T Nishimoto; T Ito
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2008-04-21
Journal Detail:
Title:  British journal of pharmacology     Volume:  154     ISSN:  0007-1188     ISO Abbreviation:  Br. J. Pharmacol.     Publication Date:  2008 Jul 
Date Detail:
Created Date:  2008-06-30     Completed Date:  2008-10-02     Revised Date:  2013-06-05    
Medline Journal Info:
Nlm Unique ID:  7502536     Medline TA:  Br J Pharmacol     Country:  England    
Other Details:
Languages:  eng     Pagination:  949-57     Citation Subset:  IM    
Affiliation:
Institute for Experimental Animals, Kobe University School of Medicine, Kobe, Japan. ieakusm@med.kobe-u.ac.jp
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MeSH Terms
Descriptor/Qualifier:
Animals
Apolipoprotein B-100 / blood
Cholesterol / blood
Collagen / metabolism
Coronary Artery Disease / enzymology,  etiology,  pathology,  prevention & control*
Disease Models, Animal
Disease Progression
Dose-Response Relationship, Drug
Enzyme Inhibitors / blood,  pharmacology*
Farnesyl-Diphosphate Farnesyltransferase / antagonists & inhibitors*,  metabolism
Hypercholesterolemia / complications,  drug therapy*,  enzymology,  pathology
Hypolipidemic Agents / blood,  pharmacology*
Image Interpretation, Computer-Assisted
Immunohistochemistry
Lipid Metabolism / drug effects
Lipoproteins, LDL / metabolism
Macrophages / drug effects*,  pathology
Male
Matrix Metalloproteinase 1 / metabolism
Oxazepines / blood,  pharmacology*
Piperidines / blood,  pharmacology*
Plasminogen Activator Inhibitor 1 / metabolism
Rabbits
Triglycerides / blood
Ubiquinone / analogs & derivatives,  metabolism
Xanthomatosis / enzymology,  etiology,  pathology,  prevention & control*
Chemical
Reg. No./Substance:
0/1-((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; 0/Apolipoprotein B-100; 0/Enzyme Inhibitors; 0/Hypolipidemic Agents; 0/Lipoproteins, LDL; 0/Oxazepines; 0/Piperidines; 0/Plasminogen Activator Inhibitor 1; 0/Triglycerides; 0/oxidized low density lipoprotein; 1339-63-5/Ubiquinone; 303-98-0/coenzyme Q10; 57-88-5/Cholesterol; 9007-34-5/Collagen; EC 2.5.1.21/Farnesyl-Diphosphate Farnesyltransferase; EC 3.4.24.7/Matrix Metalloproteinase 1
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