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Peroxynitrate-mediated DNA strand breakage activates poly(ADP-ribose) synthetase and causes cellular energy depletion in a nonseptic shock model induced by zymosan in the rat.
Shock. 1998 May; 9(5):336-40.S

Abstract

The aim of the present study was to investigate the role of poly(ADP-ribose) synthetase in a nonseptic shock model, wherein oxyradicals, nitric oxide, and peroxynitrite are known to play a crucial role in the inflammatory process. DNA single-strand breakage and activation of the nuclear enzyme poly(ADP-ribose) synthetase (PARS) triggers an energy-consuming, inefficient repair cycle, which contributes to peroxynitrite-induced cellular injury. Here we investigated whether peroxynitrite production and PARS activation are involved in cytotoxicity in macrophages collected from rats subjected to zymosan-induced shock. Macrophages harvested from the peritoneal cavity exhibited a significant production of peroxynitrite, as measured by the oxidation of the fluorescent dye dihydrorhodamine 123. Furthermore, zymosan-induced shock caused a suppression of macrophage mitochondrial respiration, DNA strand breakage, activation of PARS, and reduction of NAD+ cellular levels. In vivo treatment with 3-aminobenzamide (10 mg/kg intraperitoneally, 1 and 6 h after zymosan injection) or nicotinamide (50 mg/kg intraperitoneally, 1 and 6 h after zymosan injection) significantly inhibited the decrease in mitochondrial respiration and the activation of PARS, and partially restored the cellular level of NAD+. In a separate group of experiments, in vivo pretreatment with NG-nitro-L-arginine methyl ester, a nonselective inhibitor of nitric oxide synthesis (10 mg/kg intraperitoneally, 15 min before zymosan administration), reduced peroxynitrite formation and prevented the appearance of DNA damage, the decrease in mitochondrial respiration, and the loss of cellular levels of NAD+. Our study suggests that formation of peroxynitrite and subsequent activation of PARS may alter macrophage function in inflammatory processes and inhibition of nitric oxide, and that PARS may be a novel pharmacological approach to prevent cell injury in inflammation.

Authors+Show Affiliations

Institute of Pharmacology, School of Medicine, University of Messina, Italy.No affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

9617882

Citation

Cuzzocrea, S, et al. "Peroxynitrate-mediated DNA Strand Breakage Activates poly(ADP-ribose) Synthetase and Causes Cellular Energy Depletion in a Nonseptic Shock Model Induced By Zymosan in the Rat." Shock (Augusta, Ga.), vol. 9, no. 5, 1998, pp. 336-40.
Cuzzocrea S, Zingarelli B, Caputi AP. Peroxynitrate-mediated DNA strand breakage activates poly(ADP-ribose) synthetase and causes cellular energy depletion in a nonseptic shock model induced by zymosan in the rat. Shock. 1998;9(5):336-40.
Cuzzocrea, S., Zingarelli, B., & Caputi, A. P. (1998). Peroxynitrate-mediated DNA strand breakage activates poly(ADP-ribose) synthetase and causes cellular energy depletion in a nonseptic shock model induced by zymosan in the rat. Shock (Augusta, Ga.), 9(5), 336-40.
Cuzzocrea S, Zingarelli B, Caputi AP. Peroxynitrate-mediated DNA Strand Breakage Activates poly(ADP-ribose) Synthetase and Causes Cellular Energy Depletion in a Nonseptic Shock Model Induced By Zymosan in the Rat. Shock. 1998;9(5):336-40. PubMed PMID: 9617882.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Peroxynitrate-mediated DNA strand breakage activates poly(ADP-ribose) synthetase and causes cellular energy depletion in a nonseptic shock model induced by zymosan in the rat. AU - Cuzzocrea,S, AU - Zingarelli,B, AU - Caputi,A P, PY - 1998/6/9/pubmed PY - 1998/6/9/medline PY - 1998/6/9/entrez SP - 336 EP - 40 JF - Shock (Augusta, Ga.) JO - Shock VL - 9 IS - 5 N2 - The aim of the present study was to investigate the role of poly(ADP-ribose) synthetase in a nonseptic shock model, wherein oxyradicals, nitric oxide, and peroxynitrite are known to play a crucial role in the inflammatory process. DNA single-strand breakage and activation of the nuclear enzyme poly(ADP-ribose) synthetase (PARS) triggers an energy-consuming, inefficient repair cycle, which contributes to peroxynitrite-induced cellular injury. Here we investigated whether peroxynitrite production and PARS activation are involved in cytotoxicity in macrophages collected from rats subjected to zymosan-induced shock. Macrophages harvested from the peritoneal cavity exhibited a significant production of peroxynitrite, as measured by the oxidation of the fluorescent dye dihydrorhodamine 123. Furthermore, zymosan-induced shock caused a suppression of macrophage mitochondrial respiration, DNA strand breakage, activation of PARS, and reduction of NAD+ cellular levels. In vivo treatment with 3-aminobenzamide (10 mg/kg intraperitoneally, 1 and 6 h after zymosan injection) or nicotinamide (50 mg/kg intraperitoneally, 1 and 6 h after zymosan injection) significantly inhibited the decrease in mitochondrial respiration and the activation of PARS, and partially restored the cellular level of NAD+. In a separate group of experiments, in vivo pretreatment with NG-nitro-L-arginine methyl ester, a nonselective inhibitor of nitric oxide synthesis (10 mg/kg intraperitoneally, 15 min before zymosan administration), reduced peroxynitrite formation and prevented the appearance of DNA damage, the decrease in mitochondrial respiration, and the loss of cellular levels of NAD+. Our study suggests that formation of peroxynitrite and subsequent activation of PARS may alter macrophage function in inflammatory processes and inhibition of nitric oxide, and that PARS may be a novel pharmacological approach to prevent cell injury in inflammation. SN - 1073-2322 UR - https://www.unboundmedicine.com/medline/citation/9617882/Peroxynitrate_mediated_DNA_strand_breakage_activates_poly_ADP_ribose__synthetase_and_causes_cellular_energy_depletion_in_a_nonseptic_shock_model_induced_by_zymosan_in_the_rat_ L2 - http://ovidsp.ovid.com/ovidweb.cgi?T=JS&PAGE=linkout&SEARCH=9617882.ui DB - PRIME DP - Unbound Medicine ER -