Poly (ADP-ribose) polymerase-1 (PARP), a chromatin-bound enzyme is activated by cell oxidative stress. Since oxidative-stress is also considered a main component of angiotensin-II mediated cell-signaling, it was postulated that PARP could be a downstream target of angiotensin-II-induced signaling leading to cardiac hypertrophy. To determine a role of PARP in angiotensin-II-induced hypertrophy, we infused angiotensin-II into wild-type (PARP +/+) and PARP deficient mice. Angiotensin-II infusion significantly increased heart weight/tibia length ratio, myocyte cross sectional area and interstitial fibrosis in PARP (+/+), but not in PARP (-/-) mice. To confirm these results we analyzed the effect of angiotensin-II in primary cultures of cardiomyocytes. Compared to PARP (-/-) cardiomyocytes, angiotensin-II (1µM) treatment significantly increased protein synthesis in PARP (+/+) myocytes, as measured by ³H-lecucine incorporation into total cell protein. Angiotensin-II mediated hypertrophy of myocytes was accompanied with increased poly ADP-ribosylation of nuclear proteins and depletion of cellular NAD-content. When cells were treated with cell-death inducing doses of angiotensin-II (10-20 µM) robust myocyte cell-death was observed in PARP (+/+), but not in PARP (-/-) myocytes. This type of cell-death was blocked by repletion of cellular NAD levels as well as by activation of the longevity factor Sir2 deacetylase, indicating that PARP induction and subsequent depletion of NAD levels are the sequence of events causing angiotensin-II mediated cardiomyocyte cell-death. In conclusion, these results demonstrate that PARP is a nuclear integrator of angiotensin-II mediated cell-signaling contributing to cardiac hypertrophy and suggest that this could be a novel therapeutic target for the management of heart failure.