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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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001-es BibID:	BIBFORM028551
Első szerző:	Szabó Csaba (orvos)
Cím:	Part I : pathogenetic role of peroxynitrite in the development of diabetes and diabetic vascular complications : studies with FP15, a novel potent peroxynitrite decomposition catalyst / Csaba Szabó, Jon G. Mabley, Suzanne M. Moeller, Roman Shimanovich, Pál Pacher, László Virág, Francisco G. Soriano, John H. Van Duzer, William Williams, Andrew L. Salzman, John T. Groves
Dátum:	2002
ISSN:	1076-1551
Megjegyzések:	BACKGROUND: Peroxynitrite is a cytotoxic oxidant formed from nitric oxide (NO) and superoxide. Tyrosine nitration, a footprint of peroxynitrite, has been demonstrated in the pancreatic islets as well as in the cardiovascular system of diabetic subjects. Delineation of the pathogenetic role of peroxynitrite in disease conditions requires the use of potent, in vivo active peroxynitrite decomposition catalysts. The aim of the current work was to produce a potent peroxynitrite decomposition catalyst and to test its effects in rodent models of diabetes and its complications. METHODS: FP15 was synthesized and analyzed using standard chemical methods. Diabetes was triggered by the administration of streptozotocin. Tyrosine nitration was measured immunohistochemically. Cardiovascular and vascular measurements were conducted according to standard physiologic methods. RESULTS: FP15, a potent porphyrinic peroxynitrite decomposition catalyst, potently inhibited tyrosine nitration and peroxynitrite-induced cytotoxicity in vitro and in vivo. FP15 treatment (3-10 mg/kg/d) dose dependently and reduced the incidence and severity of diabetes mellitus in rats subjected to multiple low doses of streptozotocin, as well as in nonobese mice developing spontaneous autoimmune diabetes. Furthermore, treatment with FP15 protected against the development of vascular dysfunction (loss of endothelium-dependent relaxations) and the cardiac dysfunction (loss of myocardial contractility) in diabetic mice. FP15 treatment reduced tyrosine nitration in the diabetic pancreatic islets. CONCLUSIONS: The current results demonstrate the importance of endogenous peroxynitrite generation in the pathogenesis of autoimmune diabetes and diabetic cardiovascular complications. Peroxynitrite decomposition catalysts may be of therapeutic utility in diabetes and other pathophysiologic conditions.
Tárgyszavak:	Orvostudományok Elméleti orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban
Megjelenés:	Molecular Medicine 8 : 10 (2002), p. 571-580. -
További szerzők:	Mabley, Jon G. Moeller, Suzanne M. Shimanovich, Roman Pacher Pál Virág László (1965-) (biokémikus, sejtbiológus, farmakológus) Soriano, Francisco Garcia Van Duzer, John H. Williams, William Salzman, Andrew L. Groves, John T.
Internet cím:	Intézményi repozitóriumban (DEA) tárolt változat
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