PARP-1 inhibition does not restore oxidant-mediated reduction in SIRT1 activity.
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.
Caito
Samuel
S
Department of Environmental Medicine, University of Rochester Medical Center, Rochester, NY, USA.
Hwang
Jae-Woong
JW
Chung
Sangwoon
S
Yao
Hongwei
H
Sundar
Isaac K
IK
Rahman
Irfan
I
D000818:Animals; D002460:Cell Line; D015536:Down-Regulation; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009243:NAD / Q000378:metabolism*; D018384:Oxidative Stress; D000071137:Poly (ADP-Ribose) Polymerase-1; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism*; D056564:Sirtuin 1 / Q000378:metabolism*; D012907:Smoking / Q000378:metabolism*; D014867:Water / Q000378:metabolism
D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D014867:Water; D009243:NAD; C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; C447939:SIRT1 protein, human; D056564:Sirtuin 1