title: Potent metalloporphyrin peroxynitrite decomposition catalyst protects against the development of doxorubicin-induced cardiac dysfunction.
abstract: BACKGROUND
  Increased oxidative stress and dysregulation of nitric oxide have been implicated in the cardiotoxicity of doxorubicin (DOX), a commonly used antitumor agent. Peroxynitrite is a reactive oxidant produced from nitric oxide and superoxide in various forms of cardiac injury. Using a novel metalloporphyrinic peroxynitrite decomposition catalyst, FP15, and nitric oxide synthase inhibitors or knockout mice, we now delineate the pathogenetic role of peroxynitrite in rodent models of DOX-induced cardiac dysfunction.
  
  
  RESULTS
  Mice received a single injection of DOX (25 mg/kg IP). Five days after DOX administration, left ventricular performance was significantly depressed, and high mortality was noted. Treatment with FP15 and an inducible nitric oxide synthase inhibitor, aminoguanidine, reduced DOX-induced mortality and improved cardiac function. Genetic deletion of the inducible nitric oxide synthase gene was also accompanied by better preservation of cardiac performance. In contrast, inhibition of the endothelial isoform of nitric oxide synthase with N-nitro-L-arginine methyl ester increased DOX-induced mortality. FP15 reduced the DOX-induced increase in serum LDH and creatine kinase activities. Furthermore, FP15 prevented the DOX-induced increase in lipid peroxidation, nitrotyrosine formation, and metalloproteinase activation in the heart but not NAD(P)H-driven superoxide generation. Peroxynitrite neutralization did not interfere with the antitumor effect of DOX. FP15 also decreased ischemic injury in rats and improved cardiac function and survival of mice in a chronic model of DOX-induced cardiotoxicity.
  
  
  CONCLUSIONS
  Thus, peroxynitrite plays a key role in the pathogenesis of DOX-induced cardiac failure. Targeting peroxynitrite formation may represent a new cardioprotective strategy after DOX exposure or in other conditions associated with peroxynitrite formation, including myocardial ischemia/reperfusion injury.
authors.affiliation: Inotek Pharmaceuticals Corp, Beverly, Mass 01915, USA.
authors.forename: Pál
authors.initials: P
authors.lastname: Pacher
authors.forename: Lucas
authors.initials: L
authors.lastname: Liaudet
authors.forename: Péter
authors.initials: P
authors.lastname: Bai
authors.forename: Jon G
authors.initials: JG
authors.lastname: Mabley
authors.forename: Pawel M
authors.initials: PM
authors.lastname: Kaminski
authors.forename: László
authors.initials: L
authors.lastname: Virág
authors.forename: Amitabha
authors.initials: A
authors.lastname: Deb
authors.forename: Eva
authors.initials: E
authors.lastname: Szabó
authors.forename: Zoltán
authors.initials: Z
authors.lastname: Ungvári
authors.forename: Michael S
authors.initials: MS
authors.lastname: Wolin
authors.forename: John T
authors.initials: JT
authors.lastname: Groves
authors.forename: Csaba
authors.initials: C
authors.lastname: Szabó
mesh_terms: D000208:Acute Disease; D000818:Animals; D002384:Catalysis / Q000187:drug effects; D002908:Chronic Disease; D003402:Creatine Kinase / Q000097:blood; D004195:Disease Models, Animal; D004317:Doxorubicin / Q000633:toxicity*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006321:Heart / Q000187:drug effects* / Q000503:physiopathology; D006333:Heart Failure / Q000139:chemically induced* / Q000503:physiopathology / Q000517:prevention & control; D007770:L-Lactate Dehydrogenase / Q000097:blood; D008297:Male; D008665:Metalloporphyrins / Q000494:pharmacology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; D018384:Oxidative Stress / Q000187:drug effects / Q000235:genetics; D030421:Peroxynitrous Acid / Q000378:metabolism*; D015996:Survival Rate
chemical_list: D004791:Enzyme Inhibitors; C471469:FeCl tetrakis-2-(triethyleneglycolmonomethylether)pyridylporphyrin; D008665:Metalloporphyrins; D030421:Peroxynitrous Acid; D004317:Doxorubicin; D007770:L-Lactate Dehydrogenase; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; C496317:Nos2 protein, mouse; C496315:Nos3 protein, mouse; D003402:Creatine Kinase