title: The protective roles of nitric oxide and superoxide dismutase in adriamycin-induced cardiotoxicity.
abstract: 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.
authors.affiliation: Graduate Centers for Toxicology and Nutritional Sciences, University of Kentucky, Lexington, Kentucky, 464 Health Sciences Research Building, Lexington, KY 40536, USA.
authors.forename: Marsha P
authors.initials: MP
authors.lastname: Cole
authors.forename: Luksana
authors.initials: L
authors.lastname: Chaiswing
authors.forename: Terry D
authors.initials: TD
authors.lastname: Oberley
authors.forename: Stephanie E
authors.initials: SE
authors.lastname: Edelmann
authors.forename: Michael T
authors.initials: MT
authors.lastname: Piascik
authors.forename: Shu-Mei
authors.initials: SM
authors.lastname: Lin
authors.forename: Kinsley K
authors.initials: KK
authors.lastname: Kiningham
authors.forename: Daret K
authors.initials: DK
authors.lastname: St Clair
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000009:adverse effects*; D009202:Cardiomyopathies / Q000139:chemically induced* / Q000378:metabolism / Q000517:prevention & control; D002316:Cardiotonic Agents / Q000494:pharmacology; D003593:Cytoplasm / Q000473:pathology; D004317:Doxorubicin / Q000009:adverse effects*; D016166:Free Radical Scavengers / Q000378:metabolism*; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008929:Mitochondria, Heart / Q000473:pathology; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D009569:Nitric Oxide / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism*
chemical_list: D000903:Antibiotics, Antineoplastic; D002316:Cardiotonic Agents; D016166:Free Radical Scavengers; D009569:Nitric Oxide; D004317:Doxorubicin; D052247:Nitric Oxide Synthase Type II; D013482:Superoxide Dismutase; D007545:Isoproterenol