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Age-related myocardial apoptosis is inhibited by metallothionein in mouse
AGE-RELATED MYOCARDIAL APOPTOSIS BY METALLOTHIONEIN IN MOUSE
IS INHIBITED
&n-Xianw and Y. James Kang, Departments of Medicine, and Pharmacology & Toxicology, University of Louisville School of Medicine, Louisville, KY 40292 Our recent studies have demonstrated that metallothionein (MT), an intracellular cysteine rich and metal binding protein, plays an important role in cardiac protection against oxidative injury. Age-related detrimental alterations have been identified in multiple organ systems including myocardial tissues. Because oxidative stress is critically involved in the aging process, the present study was undertaken to test the hypothesis that age-related myocardial degeneration is inhibited in cardiac-specific MT overexpressing transgenic mice. Heart tissues were obtained from mice at age of 13 months. Myocardial ultrastructural changes were examined by electron microscopy and apoptosis was detected by a TUNEL assay and confirmed by an immunogold staining of condensed nuclei. Release of mitochondrial cytochrome c and activation of caspase-3 were detected by electron microscopy or immunohistochemistry. Evidence of apoptosis was observed and there was significant accumulation of cytochrome c in the cytosol and marked activation of caspase-3 in non-transgenic mouse hearts. These changes were all dramatically diminished in the transgenic mouse hearts. The present study thus provides in vivo evidence of MT inhibition of age-related cytochrome c-dependent activation of caspase-3 and apoptosis in myocardial tissues.
OXYGEN
’ 9
9
s47
IS INHIBITED
&n-Xianw and Y. James Kang, Departments of Medicine, and Pharmacology & Toxicology, University of Louisville School of Medicine, Louisville, KY 40292 Our recent studies have demonstrated that metallothionein (MT), an intracellular cysteine rich and metal binding protein, plays an important role in cardiac protection against oxidative injury. Age-related detrimental alterations have been identified in multiple organ systems including myocardial tissues. Because oxidative stress is critically involved in the aging process, the present study was undertaken to test the hypothesis that age-related myocardial degeneration is inhibited in cardiac-specific MT overexpressing transgenic mice. Heart tissues were obtained from mice at age of 13 months. Myocardial ultrastructural changes were examined by electron microscopy and apoptosis was detected by a TUNEL assay and confirmed by an immunogold staining of condensed nuclei. Release of mitochondrial cytochrome c and activation of caspase-3 were detected by electron microscopy or immunohistochemistry. Evidence of apoptosis was observed and there was significant accumulation of cytochrome c in the cytosol and marked activation of caspase-3 in non-transgenic mouse hearts. These changes were all dramatically diminished in the transgenic mouse hearts. The present study thus provides in vivo evidence of MT inhibition of age-related cytochrome c-dependent activation of caspase-3 and apoptosis in myocardial tissues.
OXYGEN
’ 9
9
s47