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.
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