Document Detail


Inhibiting mitochondrial fission protects the heart against ischemia/reperfusion injury.
MedLine Citation:
PMID:  20421521     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
BACKGROUND: Whether alterations in mitochondrial morphology affect the susceptibility of the heart to ischemia/reperfusion injury is unknown. We hypothesized that modulating mitochondrial morphology protects the heart against ischemia/reperfusion injury.
METHODS AND RESULTS: In response to ischemia, mitochondria in HL-1 cells (a cardiac-derived cell line) undergo fragmentation, a process that is dependent on the mitochondrial fission protein dynamin-related protein 1 (Drp1). Transfection of HL-1 cells with the mitochondrial fusion proteins mitofusin 1 or 2 or with Drp1(K38A), a dominant-negative mutant form of Drp1, increased the percentage of cells containing elongated mitochondria (65+/-4%, 69+/-5%, and 63+/-6%, respectively, versus 46+/-6% in control: n=80 cells per group; P<0.05), decreased mitochondrial permeability transition pore sensitivity (by 2.4+/-0.5-, 2.3+/-0.7-, and 2.4+/-0.3-fold, respectively; n=80 cells per group; P<0.05), and reduced cell death after simulated ischemia/reperfusion injury (11.6+/-3.9%, 16.2+/-3.9%, and 12.1+/-2.9%, respectively, versus 41.8+/-4.1% in control: n=320 cells per group; P<0.05). Treatment of HL-1 cells with mitochondrial division inhibitor-1, a pharmacological inhibitor of Drp1, replicated these beneficial effects. Interestingly, elongated interfibrillar mitochondria were identified in the adult rodent heart with confocal and electron microscopy, and in vivo treatment with mitochondrial division inhibitor-1 increased the percentage of elongated mitochondria from 3.6+/-0.5% to 14.5+/-2.8% (P=0.023). Finally, treatment of adult murine cardiomyocytes with mitochondrial division inhibitor-1 reduced cell death and inhibited mitochondrial permeability transition pore opening after simulated ischemia/reperfusion injury, and in vivo treatment with mitochondrial division inhibitor-1 reduced myocardial infarct size in mice subject to coronary artery occlusion and reperfusion (21.0+/-2.2% with mitochondrial division inhibitor-1 versus 48.0+/-4.5% in control; n=6 animals per group; P<0.05).
CONCLUSIONS: Inhibiting mitochondrial fission protects the heart against ischemia/reperfusion injury, suggesting a novel pharmacological strategy for cardioprotection.
Authors:
Sang-Bing Ong; Sapna Subrayan; Shiang Y Lim; Derek M Yellon; Sean M Davidson; Derek J Hausenloy
Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2010-04-26
Journal Detail:
Title:  Circulation     Volume:  121     ISSN:  1524-4539     ISO Abbreviation:  Circulation     Publication Date:  2010 May 
Date Detail:
Created Date:  2010-05-11     Completed Date:  2010-06-02     Revised Date:  2011-09-26    
Medline Journal Info:
Nlm Unique ID:  0147763     Medline TA:  Circulation     Country:  United States    
Other Details:
Languages:  eng     Pagination:  2012-22     Citation Subset:  AIM; IM    
Affiliation:
The Hatter Cardiovascular Institute, University College London Hospital, UK.
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MeSH Terms
Descriptor/Qualifier:
Age Factors
Animals
Cardiotonic Agents / pharmacology*
Cell Death / physiology
Cell Line
GTP Phosphohydrolases / antagonists & inhibitors,  genetics,  metabolism
Green Fluorescent Proteins / genetics
Male
Membrane Fusion / physiology
Mice
Mice, Inbred C57BL
Microscopy, Confocal
Microscopy, Electron
Microtubule-Associated Proteins / antagonists & inhibitors,  genetics,  metabolism
Mitochondria / drug effects*,  physiology,  ultrastructure
Mitochondrial Membranes / drug effects,  physiology,  ultrastructure
Myocardial Reperfusion Injury* / drug therapy,  pathology,  physiopathology
Myocytes, Cardiac* / cytology,  drug effects,  physiology
Quinazolinones / pharmacology*
Transfection
Grant Support
ID/Acronym/Agency:
//British Heart Foundation
Chemical
Reg. No./Substance:
0/3-(2,4-dichloro-5-methoxyphenyl)-2-sulfanyl-4(3H)-quinazolinone; 0/Cardiotonic Agents; 0/Microtubule-Associated Proteins; 0/Quinazolinones; 147336-22-9/Green Fluorescent Proteins; EC 3.6.1.-/GTP Phosphohydrolases; EC 3.6.1.-/Mfn1 protein, mouse; EC 3.6.1.-/Mfn2 protein, mouse; EC 3.6.5.5/Dnm1l protein, mouse

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