RRC ID 30499
Author Yao H, Sundar IK, Ahmad T, Lerner C, Gerloff J, Friedman AE, Phipps RP, Sime PJ, McBurney MW, Guarente L, Rahman I.
Title SIRT1 protects against cigarette smoke-induced lung oxidative stress via a FOXO3-dependent mechanism.
Journal Am J Physiol Lung Cell Mol Physiol
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.
Volume 306(9)
Pages L816-28
Published 2014-5-1
DOI 10.1152/ajplung.00323.2013
PII ajplung.00323.2013
PMID 24633890
PMC PMC4010647
MeSH Animals Antioxidants / metabolism Blotting, Western Female Forkhead Box Protein O3 Forkhead Transcription Factors / genetics Forkhead Transcription Factors / metabolism* Humans Lipid Peroxidation / drug effects Lung Diseases / chemically induced Lung Diseases / pathology Lung Diseases / prevention & control* Male Mice Mice, Inbred C57BL Mice, Knockout Mice, Transgenic NF-E2-Related Factor 2 / physiology Oxidative Stress* Protein Carbonylation / drug effects RNA, Messenger / genetics Real-Time Polymerase Chain Reaction Reverse Transcriptase Polymerase Chain Reaction Sirtuin 1 / physiology* Smoke / adverse effects*
IF 4.418
Times Cited 56
Mice RBRC01390