Antiapoptotic effect and inhibition of ischemia/reperfusion-induced myocardial injury in metallothionein-overexpressing transgenic mice.
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.
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D003574:Cytochrome c Group / Q000378:metabolism; D004121:Dimethyl Sulfoxide / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects; D016166:Free Radical Scavengers; D006321:Heart / Q000187:drug effects / Q000503:physiopathology; D015227:Lipid Peroxidation / Q000187:drug effects; D008668:Metallothionein / Q000378:metabolism / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009203:Myocardial Infarction / Q000473:pathology; D017202:Myocardial Ischemia / Q000473:pathology* / Q000503:physiopathology*; D015428:Myocardial Reperfusion Injury / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology*; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D051381:Rats
D003574:Cytochrome c Group; D016166:Free Radical Scavengers; D008668:Metallothionein; C505409:Casp3 protein, mouse; C505410:Casp3 protein, rat; D053148:Caspase 3; D020169:Caspases; D004121:Dimethyl Sulfoxide