Objective: Treatment with adriamycin (ADR) is associated with cardiotoxicity mediated through the generation of superoxide (O2 .-). Because nitric oxide (.NO) reacts with O 2.-, 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.
|Number of pages||12|
|State||Published - Jan 2006|
Bibliographical noteFunding Information:
We thank Dr. Judy Hines for providing the initial steps in generation of the mice and Dr. Brett Jones, Teresa Noel, and Jenny Smith for technical assistance. This work was supported by NIH grants T32DK07778, R01CA80152, R01CA94853, and fellowship support to Luksana Chai-swing from the Thailand Research fund Royal Golden Jubilee program. This research was supported by resources and facilities from the William S. Middleton Veterans Administration Hospital, Madison, WI.
ASJC Scopus subject areas
- Cardiology and Cardiovascular Medicine
- Physiology (medical)