Abstract

Overactivation of the nuclear enzyme PARP importantly contributes to the development of cell dysfunction and tissue injury in various pathophysiological conditions associated with oxidative stress, including myocardial reperfusion injury, heart transplantation, stroke, shock and diabetes. We investigated the effects of a novel ultrapotent poly(ADP-ribose) polymerase (PARP) inhibitors PJ34 and INO1001, on cardiac and endothelial dysfunction in rat models of chronic heart failure (CHF) induced by either chronic ligation of the left anterior descending coronary artery or by the administration of the cytotoxic drug doxorubicin (DOX). In the CHF model, left ventricular function and ex vivo vascular contractility and relaxation were measured 10 or 8 weeks after the surgery. Nitrotyrosine (NT) formation and PARP activation were detected by immunohistochemistry. CHF and DOX induced increased NT formation and PARP activation in the myocardium and intramural vasculature, depressed left ventricular performance and impaired vascular relaxation of aortic rings. PJ34 and INO1001 significantly improved both cardiac dysfunction and vascular relaxation and delayed CHF- and DOX associated mortality. Thus, PARP activation plays a key role in the pathogenesis of various forms of chronic heart failure. References: 1.Virág L, Szabó C: The therapeutic potential of PARP inhibition. Pharmacological Reviews, 2002; 54: 375-429 2.Soriano FG, Virág L, Jagtap P et al: Diabetic endothelial dysfunction: the role of poly (ADP-ribose) polymerase activation. Nature Medicine, 2001; 7: 108-113 3.Pacher P, Liaudet L, Soriano FG et al: The role of poly(ADP-ribose) polymerase in the development of chronic heart failure. J Am Coll Cardiol, 2002; 40: 1006-1016

Keywords: myocardial dysfunction, peroxynitrite, Heart Failure, Doxorubicin, Ischemia