Nrf2-dependent sulfiredoxin-1 expression protects against cigarette smoke-induced oxidative stress in lungs.
Oxidative stress results in protein oxidation and is involved in the pathogenesis of lung diseases such as chronic obstructive pulmonary disorder (COPD). Sulfiredoxin-1 (Srx1) catalyzes the reduction of cysteine sulfinic acid to sulfenic acid in oxidized proteins and protects them from inactivation. This study examined the mechanism of transcriptional regulation of Srx1 and its possible protective role during oxidative stress associated with COPD. Nrf2, a transcription factor known to influence susceptibility to pulmonary diseases, upregulates Srx1 expression during oxidative stress caused by cigarette smoke exposure in the lungs of mice. Disruption of Nrf2 signaling by genetic knockout in mice or RNAi in cells downregulated the expression of Srx1. In silico analysis of the 5'-promoter-flanking region of Srx1 identified multiple antioxidant-response elements (AREs) that are highly conserved. Reporter and chromatin-immunoprecipitation assays demonstrated that ARE1 at -228 is critical for the Nrf2-mediated response. Attenuation of Srx1 expression with RNAi potentiated the toxicity of hydrogen peroxide (H2O2), whereas overexpression of Srx1 protected against H2O2-mediated cell death in vitro. Immunoblot analysis revealed dramatic decreases in Srx1 expression in lungs from patients with COPD relative to nonemphysematous lungs together with a decline in Nrf2 protein. Thus, Srx1, a key Nrf2-regulated gene, contributes to protection against oxidative injury in the lung.
Singh
Anju
A
Department of Environmental Health Sciences, Johns Hopkins Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD 212045, USA.
Ling
Guoyu
G
Suhasini
Avvaru N
AN
Zhang
Ping
P
Yamamoto
Masayuki
M
Navas-Acien
Ana
A
Cosgrove
Gregory
G
Tuder
Rubin M
RM
Kensler
Thomas W
TW
Watson
Walter H
WH
Biswal
Shyam
S
D024506:5' Flanking Region / Q000235:genetics; D000818:Animals; D045744:Cell Line, Tumor; D019610:Cytoprotection / Q000235:genetics; D004847:Epithelial Cells / Q000378:metabolism* / Q000473:pathology; D005786:Gene Expression Regulation; D006801:Humans; D006861:Hydrogen Peroxide / Q000633:toxicity; D008168:Lung / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism*; D018384:Oxidative Stress / Q000235:genetics; D050862:Oxidoreductases Acting on Sulfur Group Donors / Q000235:genetics / Q000378:metabolism*; D029424:Pulmonary Disease, Chronic Obstructive / Q000209:etiology / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering; D020218:Response Elements / Q000235:genetics; D017384:Sequence Deletion; D012907:Smoking / Q000009:adverse effects; D014162:Transfection
D051267:NF-E2-Related Factor 2; D034741:RNA, Small Interfering; D006861:Hydrogen Peroxide; D050862:Oxidoreductases Acting on Sulfur Group Donors; C529381:sulfiredoxin protein, mouse; C504024:SRXN1 protein, human