Document Detail

Mitochondrial cyclophilin-D as a potential therapeutic target for post-myocardial infarction heart failure.
MedLine Citation:
PMID:  21143389     Owner:  NLM     Status:  MEDLINE    
The pharmacological inhibition or genetic ablation of cyclophilin-D (CypD), a critical regulator of the mitochondrial permeability transition pore (mPTP), confers myocardial resistance to acute ischemia-reperfusion injury, but its role in post-myocardial infarction (MI) heart failure is unknown. The aim of this study was to determine whether mitochondrial CypD is also a therapeutic target for the treatment of post-MI heart failure. Wild-type (WT) and CypD(-/-) mice were subjected to either sham surgery or permanent ligation of the left main coronary artery to induce MI, and were assessed at either 2 or 28 days to determine the long-term effects of CypD ablation. After 2 days, myocardial infarct size was smaller and left ventricular (LV) function was better preserved in CypD(-/-) mice compared to WT mice. After 28 days, when compared to WT mice, in the CypD(-/-) mice, mortality was halved, myocardial infarct size was reduced, LV systolic function was better preserved, LV dilatation was attenuated and in the remote non-infarcted myocardium, there was less cardiomyocyte hypertrophy and interstitial fibrosis. Finally, ex vivo fibroblast proliferation was found to be reduced in CypD(-/-) cardiac fibroblasts, and in WT cardiac fibroblasts treated with the known CypD inhibitors, cyclosporin-A and sanglifehrin-A. Following an MI, mice lacking CypD have less mortality, smaller infarct size, better preserved LV systolic function and undergo less adverse LV remodelling. These findings suggest that the inhibition of mitochondrial CypD may be a novel therapeutic treatment strategy for post-MI heart failure.
Shiang Y Lim; Derek J Hausenloy; Sapna Arjun; Anthony N Price; Sean M Davidson; Mark F Lythgoe; Derek M Yellon
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Journal of cellular and molecular medicine     Volume:  15     ISSN:  1582-4934     ISO Abbreviation:  J. Cell. Mol. Med.     Publication Date:  2011 Nov 
Date Detail:
Created Date:  2011-10-25     Completed Date:  2012-04-10     Revised Date:  2014-02-20    
Medline Journal Info:
Nlm Unique ID:  101083777     Medline TA:  J Cell Mol Med     Country:  England    
Other Details:
Languages:  eng     Pagination:  2443-51     Citation Subset:  IM    
Copyright Information:
© 2011 The Authors Journal of Cellular and Molecular Medicine © 2011 Foundation for Cellular and Molecular Medicine/Blackwell Publishing Ltd.
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MeSH Terms
Apoptosis / drug effects
Cell Proliferation / drug effects
Cyclophilins / antagonists & inhibitors*,  genetics,  metabolism*
Cyclosporine / pharmacology
Heart Failure / metabolism*,  physiopathology,  therapy
Heart Ventricles
Lactones / pharmacology
Mice, Knockout
Mitochondria, Heart / metabolism
Mitochondrial Membrane Transport Proteins / metabolism
Myocardial Infarction / complications*,  metabolism,  physiopathology
Spiro Compounds / pharmacology
Ventricular Dysfunction, Left / genetics,  metabolism
Ventricular Function, Left* / drug effects
Ventricular Remodeling / drug effects
Grant Support
081285//Wellcome Trust; FS/10/39/28270//British Heart Foundation; RG/08/015/26411//British Heart Foundation; RG/08/015/26411//British Heart Foundation; WT081285//Wellcome Trust; //Department of Health
Reg. No./Substance:
0/Lactones; 0/Mitochondrial Membrane Transport Proteins; 0/Spiro Compounds; 0/mitochondrial permeability transition pore; 0/sanglifehrin A; 83HN0GTJ6D/Cyclosporine; EC 5.2.1.-/Cyclophilins; EC D

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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