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Title: Manganese superoxide dismutase and inducible nitric oxide synthase modify early oxidative events in acute Adriamycin-induced mitochondrial toxicity
Authors: Luksana Chaiswing
Marsha P. Cole
Wanida Ittarat
Luke I. Szweda
Daret K. St. Clair
Terry D. Oberley
University of Wisconsin School of Medicine and Public Health
Mahidol University
University of Kentucky
Oklahoma Medical Research Foundation
Keywords: Biochemistry, Genetics and Molecular Biology;Medicine
Issue Date: 1-Jul-2005
Citation: Molecular Cancer Therapeutics. Vol.4, No.7 (2005), 1056-1064
Abstract: In the present study, we used genetically engineered B6C3 mice [mice overexpressing manganese superoxide dismutase (TgM+/+), mice in which inducible nitric oxide synthase had been inactivated (iNOSKO-/-), and crosses of these two genotypes] to study the role of manganese superoxide dismutase (MnSOD) and inducible nitric oxide synthase (iNOS) in the development of acute Adriamycin-induced cardiotoxicity. Both nontransgenic and genetically engineered mice were treated with 20 mg/kg Adriamycin and cardiac left ventricular tissues studied at 0, 3, 6, and 24 hours. Ultrastructural damage and levels of 4-hydroxy-2-nonenal (4HNE) protein adducts and 3-nitrotyrosine (3NT) were determined in cardiomyocytes using immuno-gold ultrastructural techniques. Our previous results showed that Adriamycin caused mitochondrial injury without significant nuclear or cytoplasmic damage at early time points. Interestingly, overexpression of MnSOD protected against acute mitochondrial injury, whereas deficiency in iNOS potentiated mitochondrial injury in comparison with levels of injury present in cardiomyocyte mitochondria of nontransgenic mice. In TgM+/+mice, there was a significant inverse correlation between mitochondrial injury and 4HNE/3NT levels at all time points analyzed, suggesting that reactive oxygen species/reactive nitrogen species damage products directly regulated acute Adriamycin-induced mitochondrial injury in these mice. The present studies are the first to directly quantify the effects of MnSOD and iNOS on mitochondrial injury during acute Adriamycin-induced cardiotoxicity and show extensive and specific patterns of posttranslational modifications of mitochondrial proteins following Adriamycin treatment. Copyright © 2005 American Association for Cancer Research.
ISSN: 15357163
Appears in Collections:Scopus 2001-2005

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