Antiapoptotic effect and inhibition of ischemia/reperfusion-induced myocardial injury in metallothionein-overexpressing transgenic mice

Yujian Kang, Yan Li, Xichun Sun, Xiuhua Sun

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)1579-1586
Number of pages8
JournalAmerican Journal of Pathology
Volume163
Issue number4
DOIs
StatePublished - Oct 1 2003

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Myocardial Reperfusion Injury
Metallothionein
Transgenic Mice
Ischemia
Cytochromes c
Caspase 3
Reperfusion
Myocardial Reperfusion
Myocardial Infarction
Lipid Peroxidation
Heart Ventricles
Coronary Vessels
Apoptosis
DNA Nucleotidylexotransferase
Coronary Occlusion
Dimethyl Sulfoxide
Infarction
Reactive Oxygen Species
Oxidative Stress
Thorax

All Science Journal Classification (ASJC) codes

  • Pathology and Forensic Medicine

Cite this

Antiapoptotic effect and inhibition of ischemia/reperfusion-induced myocardial injury in metallothionein-overexpressing transgenic mice. / Kang, Yujian; Li, Yan; Sun, Xichun; Sun, Xiuhua.

In: American Journal of Pathology, Vol. 163, No. 4, 01.10.2003, p. 1579-1586.

Research output: Contribution to journalArticle

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