Pharmacologic inhibition of poly(adenosine diphosphate-ribose) polymerase may represent a novel therapeutic approach in chronic heart failure

J Am Coll Cardiol. 2002 Sep 4;40(5):1006-16. doi: 10.1016/s0735-1097(02)02062-4.


Objectives: 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.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Enzyme Activation
  • Enzyme Inhibitors / pharmacology*
  • Heart Failure / drug therapy*
  • Heart Failure / physiopathology
  • Immunohistochemistry
  • Male
  • Phenanthrenes / pharmacology*
  • Poly(ADP-ribose) Polymerase Inhibitors*
  • Rats
  • Rats, Wistar
  • Tyrosine / analogs & derivatives*
  • Tyrosine / biosynthesis
  • Vasomotor System / drug effects
  • Ventricular Function, Left / drug effects


  • Enzyme Inhibitors
  • N-(oxo-5,6-dihydrophenanthridin-2-yl)-N,N-dimethylacetamide hydrochloride
  • Phenanthrenes
  • Poly(ADP-ribose) Polymerase Inhibitors
  • 3-nitrotyrosine
  • Tyrosine