title: Myocardial postischemic injury is reduced by polyADPripose polymerase-1 gene disruption.
abstract: BACKGROUND
  PolyADPribose polymerase (PARP) is activated by DNA strand breaks to catalyze the addition of ADPribose groups to nuclear proteins, especially PARP-1. Excessive polyADPribosylation leads to cell death through depletion of NAD+ and ATP.
  
  
  METHODS
  In vivo PARP activation in heart tissue slices was assayed through conversion of [33P]NAD+ into polyADPribose (PAR) following ischemia-reperfusion (I/R) and also monitored by immunohistochemical staining for PAR. Cardiac contractility, nitric oxide (NO), reactive oxygen species (ROS), NAD+ and ATP levels were examined in wild type (WT) and in PARP-1 gene-deleted (PARP-1(-/-)) isolated, perfused mouse hearts. Myocardial infarct size was assessed following coronary artery occlusion in rats treated with PARP inhibitors.
  
  
  RESULTS
  Ischemia-reperfusion (I/R) augmented formation of nitric oxide, oxygen free radicals and PARP activity. I/R induced decreases in cardiac contractility and NAD+ levels were attenuated in PARP-1(-/-) mouse hearts. PARP inhibitors reduced myocardial infarct size in rats. Residual polyADPribosylation in PARP-1(-/-) hearts may reflect alternative forms of PARP.
  
  
  CONCLUSIONS
  PolyADPribosylation from PARP-1 and other sources of enzymatic PAR synthesis is associated with cardiac damage following myocardial ischemia. PARP inhibitors may have therapeutic utility in myocardial disease.
authors.affiliation: Department of Neuroscience, Pharmacology & Molecular Science, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
authors.forename: A A
authors.initials: AA
authors.lastname: Pieper
authors.forename: T
authors.initials: T
authors.lastname: Walles
authors.forename: G
authors.initials: G
authors.lastname: Wei
authors.forename: E E
authors.initials: EE
authors.lastname: Clements
authors.forename: A
authors.initials: A
authors.lastname: Verma
authors.forename: S H
authors.initials: SH
authors.lastname: Snyder
authors.forename: J L
authors.initials: JL
authors.lastname: Zweier
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D004578:Electron Spin Resonance Spectroscopy; D004789:Enzyme Activation; D005260:Female; D006321:Heart / Q000503:physiopathology; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D018345:Mice, Knockout; D009200:Myocardial Contraction; D009203:Myocardial Infarction / Q000201:enzymology / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D017202:Myocardial Ischemia / Q000201:enzymology* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D009206:Myocardium / Q000201:enzymology* / Q000378:metabolism / Q000473:pathology*; D009243:NAD / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D015427:Reperfusion Injury / Q000201:enzymology* / Q000235:genetics / Q000378:metabolism / Q000473:pathology
chemical_list: D007527:Isoenzymes; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D017382:Reactive Oxygen Species; D009243:NAD; D009569:Nitric Oxide; D000255:Adenosine Triphosphate; D011065:Poly(ADP-ribose) Polymerases