Manganese superoxide dismutase and inducible nitric oxide synthase modify early oxidative events in acute Adriamycin-induced mitochondrial toxicity

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 À/À ), 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 Adriamycininduced 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 immunogold 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. [Mol Cancer Ther 2005;4(7):1056 -64]

Acute Doxorubicin-Induced Cardiotoxicity is Associated with Matrix Metalloproteinase-2 Alterations in Rats

“…In cardiac myocyte, MMP-2 activation is involved in the degradation of sarcomeric and cytoskeletal proteins such as troponin I, alpha-actinin, and myosin light chain, inducing acute contractile dysfunction [37]. Doxorubicin has been shown to acutely and chronically increase oxidative stress [39,40]. Therefore, the intracellular MMP-2 activation in this study could be involved in LV dysfunction.…”

Doxorubicin increases the susceptibility of brain mitochondria to Ca2+-induced permeability transition and oxidative damage

“…Therefore, several mitochondrial structures and mechanisms provide primary targets for drug-induced toxicity and cell death [9]. Indeed, it has been reported that mitochondria are the main targets of DOX-induced cardiac toxicity [10][11][12][13].…”

“…Therefore, several mitochondrial structures and mechanisms provide primary targets for drug-induced toxicity and cell death [9]. Indeed, it has been reported that mitochondria are the main targets of DOX-induced cardiac toxicity [10][11][12][13].In light of these results, the aim of this study was to evaluate the effect of DOX treatment on brain mitochondrial function and oxidative status. Our hypothesis is that in vivo DOX administration to Wistar rats results not only in decreased mitochondrial function but also in increased susceptibility to Ca 2+ -induced PTP and oxidative damage.…”

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“…The beneficial effects of MnSOD's overexpression in reversing adriamycin induced cardiotoxicity in the cardiac mitochondria have been demonstrated [12]. These findings will open the possibility of preventing cardiotoxicity that occurs during cancer treatment.…”