Pharmacologic inhibition of poly(adenosine diphosphate-ribose) polymerase may represent a novel therapeutic approach in chronic heart failure.
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.
Pacher
Pál
P
Inotek Pharmaceuticals Corporation, Beverly, Massachusetts 19105, USA.
Liaudet
Lucas
L
Mabley
Jon g
Jg
Komjáti
Katalin
K
Szabó
Csaba
C
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
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