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Titolo:
Inhibition of poly(ADP-ribose) synthetase (PARS) and protection against peroxynitrite-induced cytotoxicity by zinc chelation
Autore:
Virag, L; Szabo, C;
Indirizzi:
Childrens Hosp, Med Ctr, Div Crit Care Med, Cincinnati, OH 45229 USA Childrens Hosp Cincinnati OH USA 45229 Care Med, Cincinnati, OH 45229 USA Debrecen Univ Med, Sch Med, Dept Pathophysiol, H-4012 Debrecen, Hungary Debrecen Univ Med Debrecen Hungary H-4012 siol, H-4012 Debrecen, Hungary Inotek Corp, Cincinnati, OH 45219 USA Inotek Corp Cincinnati OH USA 45219Inotek Corp, Cincinnati, OH 45219 USA
Titolo Testata:
BRITISH JOURNAL OF PHARMACOLOGY
fascicolo: 3, volume: 126, anno: 1999,
pagine: 769 - 777
SICI:
0007-1188(199902)126:3<769:IOPS(A>2.0.ZU;2-T
Fonte:
ISI
Lingua:
ENG
Soggetto:
CELLULAR-ENERGY DEPLETION; NITRIC-OXIDE SYNTHASE; DNA STRAND BREAKAGE; PROTEIN-KINASE-C; VASCULAR CONTRACTILE; INTRACELLULAR ZN2+; ENDOTOXIC-SHOCK; IN-VIVO; APOPTOSIS; CELLS;
Keywords:
peroxynitrite; cytotoxicity; zinc; TPEN; poly (ADP-ribose) synthetase;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
48
Recensione:
Indirizzi per estratti:
Indirizzo: Szabo, C Childrens Hosp, Med Ctr, Div Crit Care Med, 3333 Burnet Ave, Cincinnati, OH Childrens Hosp 3333 Burnet Ave Cincinnati OH USA 45229 innati, OH
Citazione:
L. Virag e C. Szabo, "Inhibition of poly(ADP-ribose) synthetase (PARS) and protection against peroxynitrite-induced cytotoxicity by zinc chelation", BR J PHARM, 126(3), 1999, pp. 769-777

Abstract

1 Peroxynitrite, a potent oxidant formed by the reaction of nitric oxide and superoxide causes thymocyte necrosis, in part, via activation of the nuclear enzyme poly(ADP-ribose) synthetase (PARS). The cytotoxic PARS pathway initiated by DNA strand breaks and excessive PARS activation has been shownto deplete cellular energy pools, leading to cell necrosis. Here we have investigated the effect of tetrakis-(2-pyridylmethyl)-ethylenediamine (TPEN)a heavy metal chelator on peroxynitrite-induced cytotoxicity.2 TPEN (10 mu M) abolished cell death induced by authentic peroxynitrite (25 mu M) and the peroxynitrite generating agent 3-morpholinosidnonimine (SIN-1, 250 mu M). Preincubation of TPEN with equimolar Zn2+ but not Ca2+ or Mg2+ blocked the cytoprotective effect of the chelator.3 TPEN (10 mu M) markedly reduced the peroxynitrite-induced decrease of mitochondrial transmembrane potential, secondary superoxide production and mitochondrial membrane damage, indicating that it acts proximal to mitochondrial alterations.4 Although TPEN (1 - 300 mu M) did not scavenge peroxynitrite, it inhibited PARS activation in a dose-dependent manner.5 The cytoprotective effect of TPEN is only partly mediated via PARS inhibition, as the chelator also protected PARS-deficient thymocytes from peroxynitrite-induced death.6 While being cytoprotective against peroxynitrite-induced necrotic death,TPEN (10 mu M), similar to other agents that inhibit PARS, enhanced apoptosis (at 5-6 h after exposure), as characterized by phosphatydilserine exposure, caspase activation and DNA fragmentation.7 In conclusion, the current data demonstrate that TPEN, most likely by zinc chelation, exerts protective effects against peroxynitrite-induced necrosis. Its effects are, in part, mediated by inhibition of PARS.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 04/04/20 alle ore 13:32:29