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Published ahead of print on June 22, 2006, doi:10.1165/rcmb.2005-0325OC

Am. J. Respir. Cell Mol. Biol., Volume 35, Number 6, December 2006, 639-650

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Submitted on August 25, 2005
Revised on June 20, 2006

Glutathione Peroxidase 2, the Major Cigarette Smoke-inducible Isoform of GPX in Lungs is Regulated by Nrf2

Anju Singh1, Tirumalai Rangasamy1, Rajesh K Thimmulappa1, Hannah Lee1, William O Osburn1, Regina Brigelius-Flohe2, Thomas W Kensler3, Masayuki Yamamoto4, and Shyam Biswal3*

1 Department of Environmental Health Sciences, Johns Hopkins University, Bloomberg School of Public Health, Baltimore, MD, USA, 2 Department of Human Nutrition, German Institute of Human Nutrition, Potsdam Rehbrucke, Germany, 3 Department of Environmental Health Sciences, Johns Hopkins University, Bloomberg School of Public Health, Baltimore, MD, USA; Sidney Kimmel Comprehensive Cancer Center, Department of Oncology, Johns Hopkins University, Baltimore, MD, USA, 4 Department of Environmental Health Sciences, Johns Hopkins University, Bloomberg School of Public Health, Baltimore, MD, USA; Center for Tsukuba Advanced Research Alliance and Institute of Basic Medical Sciences, University of Tsukuba, Tsukuba, Japan

* To whom correspondence should be addressed. E-mail: sbiswal{at}jhsph.edu.

Disruption of NF-E2 related factor (Nrf2), a redox-sensitive basic leucine zipper transcription factor causes early onset and more severe emphysema due to chronic cigarette smoke. Nrf2 determines the susceptibility of lungs to cigarette smoke-induced emphysema in mice through the transcriptional induction of numerous antioxidant genes. The lungs of Nrf2-/- mice have higher oxidative stress as evident from the increased levels of lipid peroxidation (4-hydroxy-2-nonenal) and oxidative DNA damage (7, 8-dihydro-8-Oxo-2'deoxyguanosine) in response to cigarette smoke. Glutathione peroxidases (GPX) are the primary antioxidant enzymes that scavenge hydrogen peroxide and organic hydroperoxides. Among the five GPX isoforms, expression of GPX2 was significantly induced at both mRNA and protein levels in the lungs of Nrf2+/+ mice, in response to cigarette smoke. Activation of Nrf2 by specific knock down of the cytosolic inhibitor of Nrf2, Keap1, by small inhibitory RNA (siRNA) upregulated the expression of GPx2, whereas Nrf2 siRNA downregulated the expression of GPX2 in lung epithelial cells. An ARE sequence located in the 5' promoter-flanking region of exon 1 that is highly conserved between mouse, rat, and human was identified. Mutation of this ARE core sequence completely abolished the activity of promoter-reporter gene construct. The binding of Nrf2 to the GPX2 antioxidant response element was confirmed by chromatin immunoprecipation, electrophoretic mobility shift assays and site directed mutagenesis. This study shows that GPX2 is the major oxidative stress inducible cellular glutathione peroxidase isoform in the lungs and its basal as well as inducible expression is dependent on Nrf2.




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