Previous studies using a cardiac-specific metallothionein (MT)-overexpressing transgenic mouse model have established that MT protects from Adriamycin (ADR)-induced oxidative heart injury. The molecular mechanisms that underlie this cardioprotection, however, have yet to be defined. In the present study, we tested the hypothesis that MT overexpression activates cytoprotective mechanisms leading to cardiac protection from ADR toxicity. MT-transgenic mice and nontransgenic controls were treated intraperitoneally with ADR at a single dose of 20 mg/kg and sacrificed on the third day after treatment. An expression proteomic analysis involving two-dimensional gel electrophoresis and peptide mass fingerprinting was used to identify MT-induced changes in cytoprotection related proteins. We found that cytochrome c oxidase subunit Va (CCO-Va) was among several proteins that were dramatically elevated and differentially modified in response to ADR treatment in the MT-transgenic mouse heart relative to the nontransgenic controls. Differentially expressed proteins identified include enzymes of the mitochondrial electron transport chain, enzymes involved in beta-oxidation of fatty acids and glycolysis, proteins involved in cellular antioxidant defense, and proteins involved in regulation of cardiac muscle contraction.
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