title: Pharmacologic inhibition of poly(adenosine diphosphate-ribose) polymerase may represent a novel therapeutic approach in chronic heart failure.
abstract: OBJECTIVE
  We investigated the effects of a novel ultrapotent poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitor, PJ34, on cardiac and endothelial dysfunction in a rat model of chronic heart failure (CHF).
  
  
  BACKGROUND
  Overactivation of the nuclear enzyme PARP importantly contributes to the development of cell dysfunction and tissue injury in various pathophysiologic conditions associated with oxidative stress, including myocardial reperfusion injury, heart transplantation, stroke, shock, and diabetes.
  
  
  METHODS
  Chronic heart failure was induced in Wistar rats by chronic ligation of the left anterior descending coronary artery. Left ventricular (LV) function and ex vivo vascular contractility and relaxation were measured 10 weeks after the surgery. Nitrotyrosine (NT) formation and PARP activation were detected by immunohistochemistry.
  
  
  RESULTS
  Chronic heart failure induced increased NT formation and PARP activation in the myocardium and intramural vasculature, depressed LV performance, and impaired vascular relaxation of aortic rings. PJ34 significantly decreased myocardial PARP activation but not NT formation, and improved both cardiac dysfunction and vascular relaxation.
  
  
  CONCLUSIONS
  Poly(ADP-ribose) polymerase inhibition represents a novel approach for the experimental treatment of CHF.
authors.affiliation: Inotek Pharmaceuticals Corporation, Beverly, Massachusetts 19105, USA.
authors.forename: Pál
authors.initials: P
authors.lastname: Pacher
authors.forename: Lucas
authors.initials: L
authors.lastname: Liaudet
authors.forename: Jon g
authors.initials: Jg
authors.lastname: Mabley
authors.forename: Katalin
authors.initials: K
authors.lastname: Komjáti
authors.forename: Csaba
authors.initials: C
authors.lastname: Szabó
mesh_terms: D000818:Animals; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006333:Heart Failure / Q000188:drug therapy* / Q000503:physiopathology; D007150:Immunohistochemistry; D008297:Male; D010616:Phenanthrenes / Q000494:pharmacology*; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D051381:Rats; D017208:Rats, Wistar; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000096:biosynthesis; D014666:Vasomotor System / Q000187:drug effects; D016277:Ventricular Function, Left / Q000187:drug effects
chemical_list: D004791:Enzyme Inhibitors; C434926:N-(oxo-5,6-dihydrophenanthridin-2-yl)-N,N-dimethylacetamide hydrochloride; D010616:Phenanthrenes; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; C002744:3-nitrotyrosine; D014443:Tyrosine