Format

Send to

Choose Destination
Free Radic Biol Med. 2016 Mar;92:152-162. doi: 10.1016/j.freeradbiomed.2015.12.013. Epub 2015 Dec 15.

Bach1 differentially regulates distinct Nrf2-dependent genes in human venous and coronary artery endothelial cells adapted to physiological oxygen levels.

Author information

1
Cardiovascular Division, British Heart Foundation Centre of Research Excellence, Faculty of Life Sciences & Medicine, King's College London, 150 Stamford Street, London SE1 9NH, UK.
2
Genomics Centre, King's College London, 150 Stamford Street, London SE1 9NH, UK.
3
Centre for Ultrastructural Imaging, King's College London, London SE1 9NH, UK.
4
Cardiovascular Division, British Heart Foundation Centre of Research Excellence, Faculty of Life Sciences & Medicine, King's College London, 150 Stamford Street, London SE1 9NH, UK. Electronic address: giovanni.mann@kcl.ac.uk.

Abstract

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.

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

[Indexed for MEDLINE]

Publication type, MeSH terms, Substances, Grant support

Publication type

MeSH terms

Substances

Grant support

Supplemental Content

Full text links

Icon for Elsevier Science
Loading ...
Support Center