Abstract
Activation of the nuclear enzyme poly (ADP-ribose) synthetase (PARS) in response to oxidant-mediated DNA injury has been shown to play an important role in the pathogenesis of reperfusion injury. Here we investigated the role of PARS in myocardial ischemic preconditioning (IPC). Mice with or without genetic disruption of PARS and rats in the absence or presence of the PARS inhibitor 3-aminobenzamide underwent coronary occlusion and reperfusion with or without IPC. Both poly(ADP-ribose) synthetase (PARS) deficiency and ischemic preconditioning (IPC) induced protection from reperfusion injury, attenuated inflammatory mediator production, and reduced neutrophil infiltration when compared to the response in wild-type mice. Surprisingly, the protective effect of IPC not only disappeared in PARS-/- mice, but the degree of myocardial injury and inflammatory response was similar to the one seen in wild-type animals. Similarly, in the rat model of IPC, 3-aminobenzamide pretreatment blocked the beneficial effect of IPC. Myocardial NAD+ levels were maintained in the PARS-deficient mice during reperfusion, while depleted in the wild-type mice. The protection against reperfusion injury by IPC was also associated with partially preserved myocardial NAD+ levels, indicating that PARS activation is attenuated by IPC. This conclusion was further strengthened by poly(ADP-ribose) immunohistochemical measurements, demonstrating that IPC markedly inhibits PARS activation during reperfusion. The mode of IPC's action is related, at least in part, to an inhibition of PARS. This process may occur either by self-auto-ribosylation of PARS during IPC, and/or via the release of endogenous purines during IPC that inhibit PARS activation during reperfusion.
Highlights
(ADP ribose) synthetase (PARS, known as poly [ADP ribose] polymerase or PARP) is an abundant nuclear enzyme of eukaryotic cells, which has been implicated in response to DNA injury [1]
By comparing the response to ischemic preconditioning (IPC) followed by myocardial ischemia/reperfusion in wild-type and poly (ADP-ribose) synthetase (PARS)-deficient animals and in animals with or without pharmacologic inhibition of PARS, we investigated the potential role of PARS in myocardial IPC
There were no significant differences between the wild-type and PARS-deficient groups in the areas at risk
Summary
(ADP ribose) synthetase (PARS, known as poly [ADP ribose] polymerase or PARP) is an abundant nuclear enzyme of eukaryotic cells, which has been implicated in response to DNA injury [1]. When activated by DNA single-strand breaks, PARS initiates an energy-consuming cycle by transferring ADP ribose units to nuclear proteins The result of this process is a rapid depletion of the intracellular NAD1 and ATP pools which slows the rate of glycolysis and mitochondrial respiration, leading to cell necrosis [2,3]. Results: Both poly(ADP-ribose) synthetase (PARS) deficiency and ischemic preconditioning (IPC) induced protection from reperfusion injury, attenuated inflammatory mediator production, and reduced neutrophil infiltration when compared to the response in wild-type mice. The protection against reperfusion injury by IPC was associated with partially preserved myocardial NAD1 levels, indicating that PARS activation is attenuated by IPC This conclusion was further strengthened by poly(ADP-ribose) immunohistochemical measurements, demonstrating that IPC markedly inhibits PARS activation during reperfusion. This process may occur either by self-auto-ribosylation of PARS during IPC, and/or via the release of endogenous purines during IPC that inhibit PARS activation during reperfusion
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