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001-es BibID:BIBFORM014261
Első szerző:Pacher Pál
Cím:Potent metalloporphyrin peroxynitrite decomposition catalyst protects against the development of doxorubicin-induced cardiac dysfunction / Pacher, P., Liaudet, L., Bai, P., Mabley, J. G., Kaminski, P. M., Virag, L., Deb, A., Szabo, E., Ungvari, Z., Wolin, M. S., Groves, J. T., Szabo, C.
Dátum:2003
ISSN:1524-4539 (Electronic)
Megjegyzések: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. METHODS AND 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.
Tárgyszavak:Orvostudományok Elméleti orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban
Acute Disease
Animals
Catalysis/drug effects
külföldön készült közlemény
Chronic Disease
Creatine Kinase/blood
Disease Models, Animal
Doxorubicin/*toxicity
Enzyme Inhibitors/pharmacology
Heart/*drug effects/physiopathology
Heart Failure/*chemically induced/physiopathology/prevention & control
L-Lactate Dehydrogenase/blood
Male
Metalloporphyrins/*pharmacology
Mice
Mice, Inbred BALB C
Mice, Inbred C57BL
Mice, Knockout
Nitric Oxide Synthase/antagonists & inhibitors/genetics/metabolism
Nitric Oxide Synthase Type II
Nitric Oxide Synthase Type III
Oxidative Stress/drug effects/genetics
Peroxynitrous Acid/*metabolism
Survival Rate
Megjelenés:Circulation. - 107 : 6 (2003), p. 896-904. -
További szerzők:Liaudet, Lucas Bai Péter (1976-) (biokémikus) Mabley, Jon G. Kaminski, Pawel M. Virág László (1965-) (biokémikus, sejtbiológus, farmakológus) Deb, Amitabha Szabó Éva (1965-) (bőrgyógyász, kozmetológus) Ungvári Zoltán Wolin, Michael S. Groves, John T. Szabó Csaba
Internet cím:elektronikus változat
Intézményi repozitóriumban (DEA) tárolt változat
DOI
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