Modulation of Cytochrome c Oxidase-Va Is Possibly Involved in Metallothionein Protection from Doxorubicin Cardiotoxicity

• Published in: The Journal of pharmacology and experimental therapeutics Vol. 315; no. 3; pp. 1314 - 1319
• Main Authors: Merten, Kevyn E, Feng, Wenke, Zhang, Li, Pierce, William, Cai, Jian, Klein, Jon B, Kang, Y James
• Format: Journal Article
• Language: English
• Published: United States American Society for Pharmacology and Experimental Therapeutics 01.12.2005
• Subjects: Amino Acid Sequence; Animals; Antibiotics, Antineoplastic - toxicity; Doxorubicin - toxicity; Electron Transport Complex IV - chemistry; Electron Transport Complex IV - metabolism; Electrophoresis, Gel, Two-Dimensional; Heart - drug effects; Isoelectric Focusing; Metallothionein - genetics; Metallothionein - physiology; Mice; Mice, Transgenic; Molecular Sequence Data; Peptide Mapping; Proteome - analysis; Proteomics; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
• ISSN: 0022-3565; 1521-0103
• DOI: 10.1124/jpet.105.089763

Previous studies using a cardiac-specific metallothionein (MT)-overexpressing transgenic (MT-TG) mouse model have demonstrated that MT protects from doxorubicin (DOX)-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 DOX toxicity. MT-TG mice and nontransgenic wild-type (WT) controls were treated i.p. with DOX at a single dose of 20 mg/kg and sacrificed on the third day after the treatment. An expression proteomic analysis involving two-dimensional gel electrophoresis and matrix-assisted laser desorption ionization time-of-flight mass spectrometry was used to identify MT-induced changes in cytoprotection-related proteins. We identified 18 proteins that were modified by DOX treatment in the heart. These proteins included those involved in cellular antioxidant defense, enzymes of the mitochondrial electron transport chain, enzymes involved in β-oxidation of fatty acids and glycolysis, and proteins involved in regulation of cardiac muscle contraction. However, the most dominant modification by MT is the cytochrome c oxidase subunit Va (CCO-Va). In response to DOX treatment, a specific isoform of CCO-Va was enhanced in the MT-TG but not in the WT mouse hearts. Because CCO-Va is a critical component in the mitochondrial electron transport chain, the results suggest that the cardioprotective effect of MT may be related to an increased expression or a differential modification of CCO-Va.