Myocardial postischemic injury is reduced by polyADPribose polymerase-1 gene disruption

Background: PolyADPribose polymerase (PARP) is activated by DNA strand brea ks to catalyze the addition of ADPribose groups to nuclear proteins, especi ally PARP-1. Excessive polyADPribosylation leads to cell death through depl etion of NAD(+) and ATP. Materials and Methods: In vivo PARP activation in heart tissue slices was a ssayed through conversion of [P-33]NAD(+) into polyADPribose (PAR) followin g ischemia-reperfusion (I/R) and also monitored by immunohistochemical stai ning for PAR. Cardiac contractility, nitric oxide (NO), reactive oxygen spe cies (ROS), NAD(+) and ATP levels were examined in wild type (WT) and in PA RP-1 gene-deleted (PARP-1(-/-)) isolated, perfused mouse hearts. Myocardial infarct size was assessed following coronary artery occlusion in rats trea ted with PARP inhibitors. Results: Ischemia-reperfusion (I/R) augmented formation of nitric oxide, ox ygen free radicals and PARP activity. I/R induced decreases in cardiac cont ractility and NAD(+) levels were attenuated in PARP-1(-/-) mouse hearts. PA RP inhibitors reduced myocardial infarct size in rats. Residual polyADPribo sylation in PARP-1(-/-) hearts may reflect alternative forms of PARP. Conclusions: PolyADPribosylation from PARP-1 and other sources of enzymatic PAR synthesis is associated with cardiac damage following myocardial ische mia. PARP inhibitors may have therapeutic utility in myocardial disease.