Copyright © 2005, European Society of Cardiology
The protective roles of nitric oxide and superoxide dismutase in adriamycin-induced cardiotoxicity
aGraduate Centers for Toxicology and Nutritional Sciences, University of Kentucky, Lexington, Kentucky, 464 Health Sciences Research Building, Lexington, KY 40536, USA
bDepartment of Pathology, VA Hospital, University of Wisconsin, Madison, Wisconsin 53705, USA
cFaculty of Medical Technology, Mahidol University, Bangkok, Thailand 10700
dDepartment of Molecular and Biomedical Pharmacology, University of Kentucky, Lexington, Kentucky 40536, USA
eDepartment of Pharmacology, Joan C. Edwards School of Medicine, Marshall University, Huntington, WV 25704, USA
* Corresponding author. Tel.: +1 859 257 3956; fax: +1 859 323 1059. Email address: dstcl00{at}pop.uky.edu
Objective: Treatment with adriamycin (ADR) is associated with cardiotoxicity mediated through the generation of superoxide (O2·–). Because nitric oxide (·NO) reacts with O2·–, generating peroxynitrite, we hypothesized that decreased ·NO production would lead to protection in acute cardiac injury.
Methods: We investigated the role of decreased ·NO 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 wildtype 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 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 levels mediated by ADR treatment leads to increased cardiac mitochondrial injury that can be attenuated by a compensatory increase in MnSOD.
Time for primary review 28 days
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