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

Authors: Caito, Samuel; Hwang, Jae-Woong; Chung, Sangwoon; Yao, Hongwei; Sundar, Isaac K; Rahman, Irfan

Published In Biochem Biophys Res Commun, (2010 Feb 12)

Abstract: Sirtuin1 (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 H(2)O(2) 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 down-regulation and PARP-1 activation are independent events despite both enzymes sharing the same cofactor.

PubMed ID: 20060806

MeSH Terms: Animals; Cell Line; Down-Regulation; Humans; Male; Mice; Mice, Inbred C57BL; NAD/metabolism*; Oxidative Stress*; Poly (ADP-Ribose) Polymerase-1; Poly(ADP-ribose) Polymerase Inhibitors; Poly(ADP-ribose) Polymerases/metabolism*; Sirtuin 1/metabolism*; Smoking/metabolism*; Water/metabolism