Document Detail


Antiapoptotic effect and inhibition of ischemia/reperfusion-induced myocardial injury in metallothionein-overexpressing transgenic mice.
MedLine Citation:
PMID:  14507664     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Previous studies using a cardiac-specific metallothionein (MT)-overexpressing transgenic mouse model have demonstrated that MT inhibits ischemia/reperfusion-induced myocardial injury. The present study was undertaken to test the hypothesis that the MT inhibition is associated with suppression of apoptosis mediated by mitochondrial cytochrome c release and caspase-3 activation. An open-chest coronary artery occlusion and reperfusion procedure to produce ischemia/reperfusion-induced left ventricle infarction was used in MT-overexpressing transgenic mice and non-transgenic controls. After 30 minutes of ischemia, the left ventricle was reperfused to allow blood flow through the previously occluded coronary artery bed. Myocardial infarction produced after reperfusion for 4 hours was significantly reduced in the MT transgenic mice. This inhibition correlated with the antiapoptotic effect of MT, as determined by a terminal deoxynucleotidyl transferase-mediated deoxyuridine 5-triphosphate nick-end labeling assay, mitochondrial cytochrome c release and caspase-3 activation. Ischemia/reperfusion-induced lipid peroxidation was also significantly inhibited in the MT-transgenic heart. Dimethylsulfoxide, a chemical scavenger for reactive oxygen species, was used to confirm the antioxidant effect of MT and found to suppress myocardial infarction and lipid peroxidation just as MT did. This study thus demonstrates that MT suppresses ischemia/reperfusion-induced myocardial apoptosis through, at least in part, the inhibition of cytochrome c-mediated caspase-3 activation pathway. The antiapoptotic effect of MT likely results from the suppression of oxidative stress and correlates with the inhibition of myocardial infarction.
Authors:
Y James Kang; Yan Li; Xichun Sun; Xiuhua Sun
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Publication Detail:
Type:  Journal Article; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  The American journal of pathology     Volume:  163     ISSN:  0002-9440     ISO Abbreviation:  Am. J. Pathol.     Publication Date:  2003 Oct 
Date Detail:
Created Date:  2003-09-25     Completed Date:  2003-10-29     Revised Date:  2013-06-09    
Medline Journal Info:
Nlm Unique ID:  0370502     Medline TA:  Am J Pathol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1579-86     Citation Subset:  AIM; IM    
Affiliation:
Department of Medicine, University of Louisville School of Medicine, Louisville, Kentucky 40202, USA. yjkang01@athena.louisville.edu
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MeSH Terms
Descriptor/Qualifier:
Animals
Apoptosis / drug effects*
Caspase 3
Caspases / metabolism
Cytochrome c Group / metabolism
Dimethyl Sulfoxide / pharmacology
Enzyme Activation / drug effects
Free Radical Scavengers
Heart / drug effects,  physiopathology
Lipid Peroxidation / drug effects
Metallothionein / metabolism,  pharmacology*
Mice
Mice, Inbred C57BL
Mice, Transgenic
Myocardial Infarction / pathology
Myocardial Ischemia / pathology*,  physiopathology*
Myocardial Reperfusion Injury / metabolism,  pathology*,  physiopathology*
Myocardium / metabolism,  pathology
Rats
Grant Support
ID/Acronym/Agency:
HL59225/HL/NHLBI NIH HHS; HL63760/HL/NHLBI NIH HHS
Chemical
Reg. No./Substance:
0/Cytochrome c Group; 0/Free Radical Scavengers; 67-68-5/Dimethyl Sulfoxide; 9038-94-2/Metallothionein; EC 3.4.22.-/Casp3 protein, mouse; EC 3.4.22.-/Casp3 protein, rat; EC 3.4.22.-/Caspase 3; EC 3.4.22.-/Caspases
Comments/Corrections

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