title: Protection of Nrf2 against arsenite-induced oxidative damage is regulated by the cyclic guanosine monophosphate-protein kinase G signaling pathway.
abstract: Arsenite has been shown to induce a variety of oxidative damage in mammalian cells. However, the mechanisms underlying cellular responses to its adverse effects remain unknown. We previously showed that the level of Nrf2, a nuclear transcription factor significantly increased in arsenite-treated human bronchial epithelial (HBE) cells suggesting that Nrf2 is involved in responding to arsenite-induced oxidative damage. To explore how Nrf2 can impact arsenite-induced oxidative damage, in this study, we examined Nrf2 activation and its regulation upon cellular arsenite exposure as well as its effects on arsenite-induced oxidative damage in HBE cells. We found that Nrf2 mRNA and protein levels were significantly increased by arsenite in a dose- and time-dependent manner. Furthermore, we showed that over-expression of Nrf2 significantly reduced the level of arsenite-induced oxidative damage in HBE cells including DNA damage, chromosomal breakage, lipid peroxidation and depletion of antioxidants. This indicates a protective role of Nrf2 against arsenite toxicity. This was further supported by the fact that activation of Nrf2 by its agonists, tertiary butylhydroquinone (t-BHQ) and sulforaphane (SFN) resulted in the same protective effects against arsenite toxicity. Moreover, we demonstrated that arsenite-induced activation of Nrf2 was mediated by the cyclic guanosine monophosphate (cGMP)-protein kinase G (PKG) signaling pathway. This is the first evidence showing that Nrf2 protects against arsenite-induced oxidative damage through the cGMP-PKG pathway. Our study suggests that activation of Nrf2 through the cGMP-PKG signaling pathway in HBE cells may be developed as a new strategy for prevention of arsenite toxicity. © 2016 Wiley Periodicals, Inc. Environ Toxicol 32: 2004-2020, 2017.
authors: Department of Occupational and Environmental Health, West China School of Public Health, Sichuan University, Chengdu, Sichuan, People's Republic of China.|Department of Occupational and Environmental Health, School of Public Health and Management, Chongqing, People's Republic of China.
authors: Chengzhi
authors: C
authors: Chen
authors: Department of Occupational and Environmental Health, West China School of Public Health, Sichuan University, Chengdu, Sichuan, People's Republic of China.|Department of Occupational and Environmental Health, School of Public Health and Management, Chongqing, People's Republic of China.
authors: Xuejun
authors: X
authors: Jiang
authors: Department of Occupational and Environmental Health, West China School of Public Health, Sichuan University, Chengdu, Sichuan, People's Republic of China.
authors: Shiyan
authors: S
authors: Gu
authors: Department of Chemistry and Biochemistry, Florida International University, Miami, Florida, USA.
authors: Yanhao
authors: Y
authors: Lai
authors: Department of Chemistry and Biochemistry, Florida International University, Miami, Florida, USA.|Biochemistry Ph.D. Program, Florida International University, Miami, Florida, USA.|Biomolecular Sciences Institute, Florida International University, Miami, Florida, USA.
authors: Yuan
authors: Y
authors: Liu
authors: Department of Occupational and Environmental Health, West China School of Public Health, Sichuan University, Chengdu, Sichuan, People's Republic of China.
authors: Zunzhen
authors: Z
authors: Zhang
mesh_terms: D000975:Antioxidants / Q000378:metabolism; D018053:Arsenites / Q000633:toxicity*; D002460:Cell Line; D017869:Cyclic GMP-Dependent Protein Kinases / Q000378:metabolism*; D006801:Humans; D006873:Hydroquinones / Q000494:pharmacology; D017879:Isothiocyanates / Q000494:pharmacology; D051267:NF-E2-Related Factor 2 / Q000819:agonists / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects*; D015398:Signal Transduction; D013454:Sulfoxides
chemical_list: D000975:Antioxidants; D018053:Arsenites; D006873:Hydroquinones; D017879:Isothiocyanates; D051267:NF-E2-Related Factor 2; D013454:Sulfoxides; C018855:2-tert-butylhydroquinone; D017869:Cyclic GMP-Dependent Protein Kinases; C016766:sulforaphane; C015001:arsenite
keywords: Nrf2; arsenite; cGMP-PKG signaling pathway; oxidative damage