Role of poly(ADP-ribose) synthetase in inflammation and ischaemia-reperfusion.
Oxidative and nitrosative stress can trigger DNA strand breakage, which then activates the nuclear enzyme poly(ADP-ribose) synthetase (PARS). This enzyme has also been termed poly(ADP-ribose) polymerase (PARP) or poly(ADP-ribose) transferase (pADPRT). Rapid activation of the enzyme depletes the intracellular concentration of its substrate, nicotinamide adenine dinucleotide, thus slowing the rate of glycolysis, electron transport and subsequently ATP formation. This process can result in cell dysfunction and cell death. In this article, Csaba Szabó and Valina Dawson overview the impact of pharmacological inhibition or genetic inactivation of PARS on the course of oxidant-induced cell death in vitro, and in inflammation and reperfusion injury in vivo. A major trigger for DNA damage in pathophysiological conditions is peroxynitrite, a cytotoxic oxidant formed by the reaction between the free radicals nitric oxide and superoxide. The pharmacological inhibition of poly(ADP-ribose) synthetase is a novel approach for the experimental therapy of various forms of inflammation and shock, stroke, myocardial and intestinal ischaemia-reperfusion, and diabetes mellitus.
Szabó
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Division of Critical Care, Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
Dawson
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VL
D000818:Animals; D016923:Cell Death; D004249:DNA Damage; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D006801:Humans; D007249:Inflammation / Q000201:enzymology*; D009566:Nitrates / Q000378:metabolism; D016877:Oxidants / Q000378:metabolism; D018384:Oxidative Stress; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000502:physiology*; D015427:Reperfusion Injury / Q000201:enzymology*
D004791:Enzyme Inhibitors; D009566:Nitrates; D016877:Oxidants; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; C039642:peroxynitric acid; D011065:Poly(ADP-ribose) Polymerases