PARP-1 inhibition does not restore oxidant-mediated reduction in SIRT1 activity

Sirtum1 (SIRT1) deacetylase and poly(ADP-ribose)-polymerase-1 (PARP-1) respond to environmental cues, and both require NAD(+) cofactor for their enzymatic activities However, the functional link between environmental/oxidative stress-mediated activation of PARP-1 and SIRT1 through NAD(+) cofactor availability is not known We investigated whether NAD(+) depletion by PARP-1 activation plays a role in environmental stimuli/oxidant-induced reduction in SIRT1 activity. Both H2O2 and cigarette smoke (CS) decreased intracellular NAD(+) levels in vitro in lung epithelial cells and in vivo in lungs of mice exposed to CS Pharmacological PARP-1 inhibition prevented oxidant-induced NAD(+) loss and attenuated loss of SIRT1 activity Oxidants decreased SIRT1 activity in lung epithelial cells, however increasing cellular NAD(+) cofactor levels by PARP-1 inhibition or NAD(+) precursors was unable to restore SIRT1 activity. SIRT1 was found to be carbonylated by CS, which was not reversed by PARP-1 inhibition or selective SIRT1 activator Overall, these data suggest that environmental/oxidant stress-induced SIRT1 clown-regulation and PARP-1 activation are independent events despite both enzymes sharing the same cofactor (C) 2010 Elsevier Inc. All rights reserved