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Titolo:
Requirement of intracellular calcium mobilization for peroxynitrite-induced poly(ADP-ribose) synthetase activation and cytotoxicity
Autore:
Virag, L; Scott, GS; Antal-Szalmas, P; OConnor, M; Ohshima, H; Szabo, C;
Indirizzi:
Inotek Corp, Beverly, MA 01915 USA Inotek Corp Beverly MA USA 01915Inotek Corp, Beverly, MA 01915 USA 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 Med Chem, H-4012 Debrecen, Hungary Debrecen Univ Med Debrecen Hungary H-4012 Chem, H-4012 Debrecen, Hungary Debrecen Univ Med, Sch Med, Dept Internal Med 3, H-4012 Debrecen, Hungary Debrecen Univ Med Debrecen Hungary H-4012 ed 3, H-4012 Debrecen, Hungary Int Agcy Res Canc, Unit Endogenous Canc Risk Factors, F-69372 Lyon, FranceInt Agcy Res Canc Lyon France F-69372 Risk Factors, F-69372 Lyon, France
Titolo Testata:
MOLECULAR PHARMACOLOGY
fascicolo: 4, volume: 56, anno: 1999,
pagine: 824 - 833
SICI:
0026-895X(199910)56:4<824:ROICMF>2.0.ZU;2-6
Fonte:
ISI
Lingua:
ENG
Soggetto:
PERMEANT CA2+ CHELATORS; ADP-RIBOSE SYNTHETASE; DNA STRAND BREAKAGE; MITOCHONDRIAL ELECTRON-TRANSPORT; CELLULAR-ENERGY DEPLETION; NITRIC-OXIDE; VASCULAR CONTRACTILE; REPERFUSION INJURY; ENDOTOXIC-SHOCK; IN-VITRO;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
39
Recensione:
Indirizzi per estratti:
Indirizzo: Szabo, C Inotek Corp, Suite 419E,100 Cummings Ctr, Beverly, MA 01915 USA Inotek Corp Suite 419E,100 Cummings Ctr Beverly MA USA 01915 USA
Citazione:
L. Virag et al., "Requirement of intracellular calcium mobilization for peroxynitrite-induced poly(ADP-ribose) synthetase activation and cytotoxicity", MOLEC PHARM, 56(4), 1999, pp. 824-833

Abstract

Peroxynitrite is a cytotoxic oxidant produced during shock, ischemia reperfusion, and inflammation. The cellular events mediating the cytotoxic effect of peroxynitrite include activation of poly(ADP-ribose) synthetase, inhibition of mitochondrial respiration, and activation of caspase-3. The aim ofthe present study was to investigate the role of intracellular calcium mobilization in the necrotic and apoptotic cell death induced by peroxynitrite. Peroxynitrite, in a low, pathophysiologically relevant concentration (20 mu M), induces rapid (1 to 3 min) Ca2+ mobilization in thymocytes. Inhibition of this early calcium signaling by cell-permeable Ca2+ chelators [EGTA-acetoxymethyl ester (AM), 1,2-bis(2-aminophenoxy) ethane-N,N,N',N'-tetraacetic acid-AM (BAPTA-AM), 8-amino-2-[(2-amino-5-methylphenoxy) methyl] 6-methoxyquinoline- N, N, N',N'-tetraacetic acid-tetra-AM] abolished cytotoxicity as measured by propidium iodide uptake. Intracellular Ca2+ chelators also inhibited DNA single-strand breakage and activation of poly(ADP-ribose) synthase (PARS), which is a major mediator of cell necrosis in the current model. Intracellular Ca2+ chelators also protected PARS-deficient thymocytes from peroxynitrite cytotoxicity, providing evidence for a PARS-independent, Ca2+ dependent cytotoxic pathway. Chelation of intracellular Ca2+ blocked the peroxynitrite-induced decrease of mitochondrial membrane potential, secondary superoxide production, and mitochondrial membrane damage. Peroxynitrite-induced internucleosomal DNA cleavage was increased on BAPTA-AM pretreatment in the wild-type cells but decreased in the PARS-deficient cells. Two other apoptotic parameters (phosphatidylserine exposure and caspase 3 activation) were inhibited by BAPTA-AM in both the wild-type and the PARS-deficient thymocytes. Our findings provide evidence for the pivotal role of an early Ca2+ signaling in peroxynitrite cytotoxicity.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 05/04/20 alle ore 08:07:04