title: Activation of poly(ADP-ribose) polymerase in circulating leukocytes during myocardial infarction.
abstract: Myocardial ischemia-reperfusion can lead to increased oxidative stress both locally and in circulating leukocytes. Oxidant-mediated DNA single strand breaks are known to activate the nuclear enzyme poly(ADP-ribose) polymerase (PARP) in various forms of shock, inflammation, and ischemia-reperfusion injury. The aim of the current study was to investigate whether a local insult such as myocardial ischemia-reperfusion is sufficient to lead to activation of PARP in circulating leukocytes. In anesthetized rats myocardial ischemia-reperfusion was induced by transient ligation of the left anterior descending coronary artery. There was a marked increase in poly(ADP-ribosyl)ation of proteins in homogenates of leukocytes isolated from rats at the end of the reperfusion period. Poly(ADP-ribosyl)ation was inhibited by administration of the pharmacologic PARP inhibitor INO-1001 (30 mg/kg) to the rats. We conclude that local insults, such as myocardial reperfusion injury, are sufficient to activate PARP in circulating leukocytes. PARP activation in circulating cells may mediate certain systemic effects of local ischemia-reperfusion injury such as inflammatory mediator production and remote organ injury.
authors.affiliation: Inotek Pharmaceuticals Corporation, Beverly, MA 01915, USA.
authors.forename: Kanneganti G K
authors.initials: KG
authors.lastname: Murthy
authors.forename: Chun-Yang
authors.initials: CY
authors.lastname: Xiao
authors.forename: Jon G
authors.initials: JG
authors.lastname: Mabley
authors.forename: Min
authors.initials: M
authors.lastname: Chen
authors.forename: Csaba
authors.initials: C
authors.lastname: Szabó
mesh_terms: D000818:Animals; D015153:Blotting, Western; D045744:Cell Line, Tumor; D004247:DNA / Q000378:metabolism; D004249:DNA Damage; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004847:Epithelial Cells / Q000378:metabolism; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology; D007249:Inflammation; D007962:Leukocytes / Q000201:enzymology* / Q000378:metabolism; D008297:Male; D009203:Myocardial Infarction / Q000378:metabolism*; D009206:Myocardium / Q000201:enzymology / Q000473:pathology; D011065:Poly(ADP-ribose) Polymerases / Q000097:blood / Q000378:metabolism*; D011233:Precipitin Tests; D051381:Rats; D017208:Rats, Wistar; D015427:Reperfusion Injury; D013997:Time Factors
chemical_list: D004791:Enzyme Inhibitors; C491685:INO 1001; D007211:Indoles; D004247:DNA; D006861:Hydrogen Peroxide; D011065:Poly(ADP-ribose) Polymerases