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.

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

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