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The effects of physiological oxygen tension on Nuclear Factor-E2-Related Factor 2 (Nrf2)-regulated redox signaling remain poorly understood. We report the first study of Nrf2-regulated signaling in human primary endothelial cells (EC) adapted long-term to physiological O2 (5%). Adaptation of EC to 5% O2 had minimal effects on cell ultrastructure, viability, basal redox status or HIF1-α expression. Affymetrix array profiling and subsequent qPCR/protein validation revealed that induction of select Nrf2 target genes, HO-1 and NQO1, was significantly attenuated in cells adapted to 5% O2, despite nuclear accumulation and DNA binding of Nrf2. Diminished HO-1 induction under 5% O2 was stimulus independent and reversible upon re-adaptation to air or silencing of the Nrf2 repressor Bach1, notably elevated under 5% O2. Induction of GSH-related genes xCT and GCLM were oxygen and Bach1-insensitive during long-term culture under 5% O2, providing the first evidence that genes related to GSH synthesis mediate protection afforded by Nrf2-Keap1 defense pathway in cells adapted to physiological O2 levels encountered in vivo.

Original publication

DOI

10.1016/j.freeradbiomed.2015.12.013

Type

Journal article

Journal

Free Radic Biol Med

Publication Date

03/2016

Volume

92

Pages

152 - 162

Keywords

Bach1, Coronary artery, Endothelial cells, GCL, Glutathione, Glutathione reductase GR, HO-1, Mitochondria, NQO1, Normoxia, Nuclear Factor-E2-Related Factor 2, Nrf2, Physiological oxygen tension, Redox signaling, Sequestosome-1, Solute Carrier Family 7-anionic amino acid transporter light chain xCT, Thioredoxin reductase-1, Amino Acid Transport System y+, Antioxidants, Basic-Leucine Zipper Transcription Factors, Coronary Vessels, DNA-Binding Proteins, Endothelial Cells, Fanconi Anemia Complementation Group Proteins, Glutamate-Cysteine Ligase, Glutathione, Heme Oxygenase-1, Humans, Hypoxia-Inducible Factor 1, alpha Subunit, Kelch-Like ECH-Associated Protein 1, NAD(P)H Dehydrogenase (Quinone), NF-E2-Related Factor 2, Oxygen, Reactive Oxygen Species, Veins