Poly(ADP-ribose) polymerase-1-dependent cardiac myocyte cell death during heart failure is mediated by NAD+ depletion and reduced Sir2alpha deacetylase activity

摘要: Robust activation of poly(ADP-ribose) polymerase-1 (PARP) by oxidative stress has been implicated as a major cause caspase-independent myocyte cell death contributing to heart failure. Here, we show that depletion NAD levels and the subsequent reduction Sir2alpha deacetylase activity are sequential steps PARP-mediated death. In both failing hearts cultured cardiac myocytes, increased PARP was associated with cellular reduced activity. Myocyte induced prevented repletion either adding directly culture medium or overexpressing biosynthetic enzymes. The beneficial effect seen, however, only when intact. Knocking down small interfering RNA eliminated this benefit, indicating is downstream target replenishment leading protection. also loss transcriptional regulatory catalytic core domain resulting from activation. We concomitant in regulate post-translational acetylation p53. These data demonstrate that, stressed forms link between activity, during