Abstract

The current proposal is aimed at investigating the role of the nuclear enzyme poly (ADP-ribose) synthetase (PARS) in the pathophysiology of myocardial ischemia-reperfusion injury. First, it will be established whether pharmacological inhibition of PARS ameliorates the cellular energetic derangement and the functional alterations during myocardial ischemia-reperfusion injury. This hypothesis will be tested in in vitro perfused heart preparations and in a mouse model of myocardial ischemia-reperfusion injury by correlating DNA strand-breakage, PARS activity, intracellular energetics, and myocardial contractility. PARS will be inhibited by pharmacological and molecular biological approaches. For the pharmacological approach, 3-aminobenzamide, a prototypical inhibitor of PARS will be used. Moreover, responses will be compared in hearts of wild-type mice and of knock-out mice lacking the functional PARS enzyme. The relative contribution of hydroxyl radical versus peroxynitrite in the activation of PARS in myocardial ischemia-reperfusion will also be addressed using pharmacological inhibitors. The principal investigator will also investigate the changes in endothelial function during myocardial reperfusion injury, and the role of PARS in these changes.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
7R01HL059266-02
Application #
2857941
Study Section
Cardiovascular and Pulmonary Research A Study Section (CVA)
Project Start
1999-01-01
Project End
2000-12-31
Budget Start
1999-01-01
Budget End
1999-12-31
Support Year
2
Fiscal Year
1999
Total Cost
Indirect Cost

  Institution

Name
Inotek Pharmaceuticals Corporation
Department
Type
DUNS #
City
Beverly
State
MA
Country
United States
Zip Code
01915

  Publications

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
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
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
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
Murthy, Kanneganti G K; Xiao, Chun-Yang; Mabley, Jon G et al. (2004) Activation of poly(ADP-ribose) polymerase in circulating leukocytes during myocardial infarction. Shock 21:230-4

Showing the most recent 10 out of 34 publications