The current competing continual application is aimed at advancing our studies on the role of the nuclear enzyme poly (ADP-ribose) synthetase (PARS) in the pathogenesis of myocardial reperfusion injury. In the prior funding cycle, we showed that free radical and oxidant induced activation of PARS initiates an energy consuming inefficient cellular metabolic cycle, with resultant depletion of dinucleotide pools, slowing the rate of glycolysis and mitochondrial respiration, reducing ATP synthesis and cell injury. We demonstrated that PARS activation is a major component of myocardial ischemia-reperfusion injury. In animals in which PARS was inhibited or inactivated, a significant improvement in survival, and reduction in myocardial necrosis was observed. This response was associated with a reduction of infiltrating neutrophil accumulation in the reperfused myocardium, and a marked down-regulation of the pro-inflammatory mediator production. Furthermore, in a study utilizing a murine working heart model, hearts from the PARS deficient mice were found resistant against global ischemia-reoxygenation, when compared to wild-type hearts. We have compiled preliminary data that suggest that the mode of PARS inhibition's cardioprotective action may be related to inhibition of oxidant-induced cell necrosis.
The first aim of the current grant application is to perform in vitro studies to understand the cellular mode of oxidant-induced cardiac myocyte death in response to oxidants, and to delineate the role of PARS in modulating necrosis vs. apoptosis.
The second aim i s to investigate, in in vivo studies of myocardial ischemia and reperfusion, the shift between normal, apoptotic and necrotic myocyte phenotype in the presence vs. absence of functional PARS. In the third aim, we will identify the nature and the sources of the oxygen and nitrogen centered free radical and oxidant species responsible for the activation of PARS in myocardial ischemia reperfusion. Based on interesting new preliminary data, the fourth aim is focusing on the role of endogenous purines in modulating PARS activation in myocardial reperfusion injury. Further, based on exciting preliminary data, the final, fifth aim is focusing in establishing the role of PARS in myocardial preconditioning.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL059266-05
Application #
6620979
Study Section
Cardiovascular and Pulmonary Research A Study Section (CVA)
Program Officer
Balshaw, David M
Project Start
1998-01-01
Project End
2005-11-30
Budget Start
2002-12-01
Budget End
2003-11-30
Support Year
5
Fiscal Year
2003
Total Cost
$262,500
Indirect Cost
Name
Inotek Pharmaceuticals Corporation
Department
Type
DUNS #
090253571
City
Beverly
State
MA
Country
United States
Zip Code
01915
Szabo, Gabor; Stumpf, Nicole; Radovits, Tamas et al. (2006) Effects of inosine on reperfusion injury after heart transplantation. Eur J Cardiothorac Surg 30:96-102
Pacher, Pal; Liaudet, Lucas; Mabley, Jon G et al. (2006) Beneficial effects of a novel ultrapotent poly(ADP-ribose) polymerase inhibitor in murine models of heart failure. Int J Mol Med 17:369-75
Mabley, Jon G; Horvath, Eszter M; Murthy, Kanneganti G K et al. (2005) Gender differences in the endotoxin-induced inflammatory and vascular responses: potential role of poly(ADP-ribose) polymerase activation. J Pharmacol Exp Ther 315:812-20
Mabley, Jon G; Pacher, Pal; Deb, Amitabha et al. (2005) Potential role for 8-oxoguanine DNA glycosylase in regulating inflammation. FASEB J 19:290-2
Xiao, Chun-Yang; Chen, Min; Zsengeller, Zsuzsanna et al. (2005) Poly(ADP-Ribose) polymerase promotes cardiac remodeling, contractile failure, and translocation of apoptosis-inducing factor in a murine experimental model of aortic banding and heart failure. J Pharmacol Exp Ther 312:891-8
Szenczi, Orsolya; Kemecsei, Peter; Holthuijsen, Max F J et al. (2005) Poly(ADP-ribose) polymerase regulates myocardial calcium handling in doxorubicin-induced heart failure. Biochem Pharmacol 69:725-32
Szabo, Csaba (2005) Cardioprotective effects of poly(ADP-ribose) polymerase inhibition. Pharmacol Res 52:34-43
Szabo, Gabor; Soos, Pal; Mandera, Susanne et al. (2004) Mesenteric injury after cardiopulmonary bypass: role of poly(adenosine 5'-diphosphate-ribose) polymerase. Crit Care Med 32:2392-7
Bai, Peter; Mabley, Jon G; Liaudet, Lucas et al. (2004) Matrix metalloproteinase activation is an early event in doxorubicin-induced cardiotoxicity. Oncol Rep 11:505-8
Szabo, Gabor; Liaudet, Lucas; Hagl, Siegfried et al. (2004) Poly(ADP-ribose) polymerase activation in the reperfused myocardium. Cardiovasc Res 61:471-80

Showing the most recent 10 out of 34 publications