title: SIRT1 protects against cigarette smoke-induced lung oxidative stress via a FOXO3-dependent mechanism.
abstract: Oxidative and carbonyl stress is increased in lungs of smokers and patients with chronic obstructive pulmonary disease (COPD), as well as in cigarette smoke (CS)-exposed rodent lungs. We previously showed that sirtuin1 (SIRT1), an antiaging protein, is reduced in lungs of CS-exposed mice and patients with COPD and that SIRT1 attenuates CS-induced lung inflammation and injury. It is not clear whether SIRT1 protects against CS-induced lung oxidative stress. Therefore, we determined the effect of SIRT1 on lung oxidative stress and antioxidants in response to CS exposure using loss- and gain-of-function approaches, as well as a pharmacological SIRT1 activation by SRT1720. We found that CS exposure increased protein oxidation and lipid peroxidation in lungs of wild-type (WT) mice, which was further augmented in SIRT1-deficient mice. Furthermore, both SIRT1 genetic overexpression and SRT1720 treatment significantly decreased oxidative stress induced by CS exposure. FOXO3 deletion augmented lipid peroxidation products but reduced antioxidants in response to CS exposure, which was not affected by SRT1720. Interestingly, SRT1720 treatment exhibited a similar effect on lipid peroxidation and antioxidants (i.e., manganese superoxide dismutase, heme oxygenase-1, and NADPH quinone oxidoreductase-1) in WT and nuclear factor (erythroid-derived 2)-like 2 (Nrf2)-deficient mice in response to CS exposure. This indicates that SIRT1 protects against CS-induced oxidative stress, which is mediated by FOXO3, but is independent of Nrf2. Overall, these findings reveal a novel function of SIRT1, which is to reduce CS-induced oxidative stress, and this may contribute to its protective effects against lung inflammation and subsequent development of COPD.
authors.affiliation: Dept. of Environmental Medicine, Univ. of Rochester Medical Center, Box 850, 601 Elmwood Ave., Rochester, NY 14642. irfan_rahman@urmc.rochester.edu.
authors.forename: Hongwei
authors.initials: H
authors.lastname: Yao
authors.forename: Isaac K
authors.initials: IK
authors.lastname: Sundar
authors.forename: Tanveer
authors.initials: T
authors.lastname: Ahmad
authors.forename: Chad
authors.initials: C
authors.lastname: Lerner
authors.forename: Janice
authors.initials: J
authors.lastname: Gerloff
authors.forename: Alan E
authors.initials: AE
authors.lastname: Friedman
authors.forename: Richard P
authors.initials: RP
authors.lastname: Phipps
authors.forename: Patricia J
authors.initials: PJ
authors.lastname: Sime
authors.forename: Michael W
authors.initials: MW
authors.lastname: McBurney
authors.forename: Leonard
authors.initials: L
authors.lastname: Guarente
authors.forename: Irfan
authors.initials: I
authors.lastname: Rahman
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D015153:Blotting, Western; D005260:Female; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D015227:Lipid Peroxidation / Q000187:drug effects; D008171:Lung Diseases / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D051267:NF-E2-Related Factor 2 / Q000502:physiology; D018384:Oxidative Stress; D050050:Protein Carbonylation / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D056564:Sirtuin 1 / Q000502:physiology*; D012906:Smoke / Q000009:adverse effects*
chemical_list: D000975:Antioxidants; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; C474033:FoxO3 protein, mouse; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D012333:RNA, Messenger; D012906:Smoke; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1
keywords: FOXO3; antioxidants; chronic obstructive pulmonary disease; lipid peroxidation; nuclear erythroid-related factor 2; oxidative stress