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001-es BibID:	BIBFORM014288
Első szerző:	Pacher Pál
Cím:	Activation of poly(ADP-ribose) polymerase contributes to development of doxorubicin-induced heart failure / Pacher P., Liaudet L., Bai P., Virag L., Mabley J. G., Haskó G., Szabó C.
Dátum:	2002
ISSN:	0891-5849 (Print)
Megjegyzések:	Activation of the nuclear enzyme poly(ADP-ribose) polymerase (PARP) by oxidant-mediated DNA damage is an important pathway of cell dysfunction and tissue injury in conditions associated with oxidative stress. Increased oxidative stress is a major factor implicated in the cardiotoxicity of doxorubicin (DOX), a widely used antitumor anthracycline antibiotic. Thus, we hypothesized that the activation of PARP may contribute to the DOX-induced cardiotoxicity. Using a dual approach of PARP-1 suppression, by genetic deletion or pharmacological inhibition with the phenanthridinone PARP inhibitor PJ34, we now demonstrate the role of PARP in the development of cardiac dysfunction induced by DOX. PARP-1+/+ and PARP-1-/- mice received a single injection of DOX (25 mg/kg i.p). Five days after DOX administration, left ventricular performance was significantly depressed in PARP-1+/+ mice, but only to a smaller extent in PARP-1-/- ones. Similar experiments were conducted in BALB/c mice treated with PJ34 or vehicle. Treatment with a PJ34 significantly improved cardiac dysfunction and increased the survival of the animals. In addition PJ34 significantly reduced the DOX-induced increase in the serum lactate dehydrogenase and creatine kinase activities but not metalloproteinase activation in the heart. Thus, PARP activation contributes to the cardiotoxicity of DOX. PARP inhibitors may exert protective effects against the development of severe cardiac complications associated with the DOX treatment.Nitroxyl (NO(-)/HNO), has been proposed to be one of the NO(*)-derived cytotoxic species. Although the biological effect of nitroxyl is largely unknown, it has been reported to cause DNA breakage and cytotoxicity. We have therefore investigated whether NO(-)/HNO-induced DNA single-strand breakage activates the nuclear nick sensor enzyme poly(ADP-ribose) polymerase (PARP) and whether PARP activation affects the mode of NO(-)/HNO- induced cell death. NO(-)/HNO generated from Angeli's salt (AS, sodium trioxodinitrate) (0-300 microM) induced DNA single-strand breakage, PARP activation, and a concentration-dependent cytotoxicity in murine thymocytes. AS-induced cell death was also accompanied by decreased mitochondrial membrane potential and increased secondary superoxide production. The cytotoxicity of AS, as measured by propidium iodide uptake, was abolished by electron acceptors potassium ferricyanide, TEMPOL, the intracellular calcium chelator BAPTA-AM, and by PARP inhibitors 3-aminobenzamide (3-AB) and PJ-34. The cytoprotective effect of 3-AB was paralleled by increased output of AS-induced apoptotic parameters such as phosphatidylserine exposure, caspase activation, and DNA fragmentation. No significant increase in tyrosine nitration could be observed in AS-treated thymocytes as opposed to peroxynitrite-treated cells, indicating that tyrosine nitration is not likely to contribute to NO(-)/HNO-induced cytotoxicity. Our results demonstrate that NO(-)/HNO-induced PARP activation shifts the default apoptotic cell death toward necrosis in thymocytes. However, as total PARP inhibition resulted only in 30% cytoprotection, PARP-independent mechanisms dominate NO(-)/HNO-induced cytotoxicity in thymocytes.
Tárgyszavak:	Orvostudományok Elméleti orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban Acute Disease Animals Antibiotics, Antineoplastic Creatine Kinase/metabolism Doxorubicin Enzyme Activation/drug effects Heart Failure/ chemically induced/pathology/physiopathology Hemodynamics/drug effects L-Lactate Dehydrogenase/metabolism Male Metalloendopeptidases/metabolism Mice Mice, Inbred BALB C Mice, Knockout Poly(ADP-ribose) Polymerases/ genetics/ metabolism Survival Analysis Ventricular Function, Left/genetics Apoptosis Benzamides/ pharmacology Caspases/metabolism Cells, Cultured DNA Damage/drug effects DNA Fragmentation/drug effects Enzyme Activation/drug effects/physiology Enzyme Inhibitors/ pharmacology Mice, Inbred C57BL Mitochondria/ drug effects Nitrates Nitrites/toxicity Nitrogen Oxides/ toxicity Poly(ADP-ribose) Polymerases/ antagonists & inhibitors/metabolism Protective Agents/ pharmacology Thymus Gland/cytology/ drug effects Tyrosine
Megjelenés:	The Journal of Pharmacology and Experimental Therapeutics. - 300 : 3 (2002), p. 862-867. -
További szerzők:	Liaudet, Lucas Bai Péter (1976-) (biokémikus) Virág László (1965-) (biokémikus, sejtbiológus, farmakológus) Mabley, Jon G. Haskó György (1967-) (biokémikus) Szabó Csaba
Internet cím:	Intézményi repozitóriumban (DEA) tárolt változat DOI
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