The protective roles of nitric oxide and superoxide dismutase in adriamycin-induced cardiotoxicity

Objective: Treatment with adriamycin (ADR) is associated with cardiotoxicity mediated through the generation of superoxide (O-2(center dot-)). Because nitric oxide ((NO)-N-center dot) reacts with O-2(center dot-), generating peroxynitrite, we hypothesized that decreased (NO)-N-center dot production would lead to protection in acute cardiac injury. Methods: We investigated the role of decreased (NO)-N-center dot levels in exacerbation of ADR-induced cardiotoxicity in vivo using iNOS (-/-) mice. Pathology, biochemical injury markers, and cardiac function were used to assess ADR-induced cardiac injury. Results: Ultrastructural analysis demonstrated that iNOS (-/-) mice exhibited extensive cytoplasmic swelling and degeneration of mitochondria when compared to wildlype mice following treatment with ADR. Mice lacking iNOS exhibited a decrease in resting indices of cardiac function as well as an impairment in the positive inotropic actions of isoproterenol following treatment with ADR compared to nTg mice. Cardiac troponin, creatine phosphokinase, and lactate dehydrogenase levels were significantly increased after treatment in iNOS mice as compared to controls and wildtype mice. Conclusions: These results indicate that a lack of (NO)-N-center dot production by iNOS caused significantly enhanced cardiac injury. However, when iNOS (-/-) mice were crossed with manganese superoxide dismutase (MnSOD)-overexpressing animals, mitochondrial injury was ameliorated to the level of the wild type. These findings suggest that reduction of (NO)-N-center dot levels mediated by ADR treatment leads to increased cardiac mitochondrial injury that can be attenuated by a compensatory increase in MnSOD. (c) 2005 European Society of Cardiology. Published by Elsevier B.V. All rights reserved.