title: Myocardial ischemic preconditioning in rodents is dependent on poly (ADP-ribose) synthetase.
abstract: BACKGROUND
  Activation of the nuclear enzyme poly (ADP-ribose) synthetase (PARS) in response to oxidant-mediated DNA injury has been shown to play an important role in the pathogenesis of reperfusion injury. Here we investigated the role of PARS in myocardial ischemic preconditioning (IPC).
  
  
  METHODS
  Mice with or without genetic disruption of PARS and rats in the absence or presence of the PARS inhibitor 3-aminobenzamide underwent coronary occlusion and reperfusion with or without IPC.
  
  
  RESULTS
  Both poly(ADP-ribose) synthetase (PARS) deficiency and ischemic preconditioning (IPC) induced protection from reperfusion injury, attenuated inflammatory mediator production, and reduced neutrophil infiltration when compared to the response in wild-type mice. Surprisingly, the protective effect of IPC not only disappeared in PARS-/- mice, but the degree of myocardial injury and inflammatory response was similar to the one seen in wild-type animals. Similarly, in the rat model of IPC, 3-aminobenzamide pretreatment blocked the beneficial effect of IPC. Myocardial NAD+ levels were maintained in the PARS-deficient mice during reperfusion, while depleted in the wild-type mice. The protection against reperfusion injury by IPC was also associated with partially preserved myocardial NAD+ levels, indicating that PARS activation is attenuated by IPC. This conclusion was further strengthened by poly(ADP-ribose) immunohistochemical measurements, demonstrating that IPC markedly inhibits PARS activation during reperfusion.
  
  
  CONCLUSIONS
  The mode of IPC's action is related, at least in part, to an inhibition of PARS. This process may occur either by self-auto-ribosylation of PARS during IPC, and/or via the release of endogenous purines during IPC that inhibit PARS activation during reperfusion.
authors.affiliation: Inotek Corporation, Beverly, Massachusetts 01915, USA.
authors.forename: L
authors.initials: L
authors.lastname: Liaudet
authors.forename: Z
authors.initials: Z
authors.lastname: Yang
authors.forename: E B
authors.initials: EB
authors.lastname: Al-Affar
authors.forename: C
authors.initials: C
authors.lastname: Szabó
mesh_terms: D000818:Animals; D001549:Benzamides / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007150:Immunohistochemistry; D016753:Interleukin-10 / Q000097:blood; D018664:Interleukin-12 / Q000097:blood; D019157:Ischemic Preconditioning, Myocardial; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D015428:Myocardial Reperfusion Injury / Q000201:enzymology / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D009206:Myocardium / Q000201:enzymology* / Q000378:metabolism / Q000473:pathology; D009243:NAD / Q000378:metabolism; D009195:Peroxidase / Q000378:metabolism; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D014020:Tissue Extracts; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000378:metabolism
chemical_list: D001549:Benzamides; D004791:Enzyme Inhibitors; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D014020:Tissue Extracts; D014409:Tumor Necrosis Factor-alpha; D009243:NAD; D016753:Interleukin-10; D018664:Interleukin-12; C002744:3-nitrotyrosine; D014443:Tyrosine; C025160:3-aminobenzamide; D009195:Peroxidase; D011065:Poly(ADP-ribose) Polymerases