The Hypoxia-Inducible Factor-2α Is Stabilized by Oxidative Stress Involving NOX4
Abstract
The hypoxia-inducible factor-2alpha (HIF-2alpha) contributes to the vascular response to hypoxia. Hypoxia inhibits prolyl hydroxylation of the N-terminal transactivation domain (N-TAD), thus preventing binding of the von Hippel-Lindau protein (pVHL) and proteasomal degradation; additionally, hypoxia inhibits asparagyl hydroxylation of the C-TAD, thus diminishing cofactor recruitment. Reactive oxygen species (ROS) derived from NADPH oxidases (NOXs) have been shown to control vascular functions and to promote vascular remodeling. However, whether HIF-2alpha, ROS, and NOXs are linked under such nonhypoxic conditions is unclear. We found that activation of NOX4 by thrombin or H(2)O(2) increased HIF-2alpha protein because of decreased pVHL binding in pulmonary artery smooth muscle cells (PASMCs). Thrombin, H(2)O(2), and NOX4 overexpression increased HIF-2alpha N-TAD and C-TAD activity, which was prevented by ascorbate treatment or mutation of the hydroxylation sites in the TADs. HIF-2alpha also mediated induction of plasminogen activator inhibitor-1 and the proliferative response to thrombin, H(2)O(2), or NOX4 overexpression. Thus, ROS derived from NOX4 in response to thrombin stabilize HIF-2alpha by preventing hydroxylation of the N- and C-TAD, thus allowing formation of transcriptionally active HIF-2alpha, which promotes PASMC proliferation. Together, these findings present the first evidence that HIF-2alpha is critically involved in the ROS-regulated vascular remodeling process…
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ROS-dependent modulation of PHD2 activity under mild hypoxia alters hydroxylase function without complete oxygen withdrawal.
“This framework was further refined by studies identifying ROS-dependent modulation of PHD2 activity under mild hypoxia, in which oxidative modification alters hydroxylase function without complete oxygen withdrawal [207,208].”
From HIF inhibition: Current strategies and clinical challenges (2026) · cites this paper as [207]
HIF stabilization frequently reflects redox-controlled tuning of oxygen-sensing enzymes within a permissive oxygen range, rather than absolute hypoxia.
“Together, these data provide a mechanistic explanation for pseudohypoxia and support the view that HIF stabilization frequently reflects redox-controlled tuning of oxygen-sensing enzymes within a permissive oxygen range, rather than absolute hypoxia.”
From HIF inhibition: Current strategies and clinical challenges (2026) · cites this paper as [207]
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HIF inhibition: Current strategies and clinical challenges
Więch-Walów, A., Bartoszewska, S., Barton, A., Czechowicz, P., Dudzik, J., Wielockx, B., Collawn, J. F., & Bartoszewski, R. (2026) · Redox biology · doi:10.1016/j.redox.2026.104220 · Cited by 3 · see citing works
- Authors
- Diebold, I., Flügel, D., Becht, S., BelAiba, R. S., Bonello, S., Hess, J., Kietzmann, T., & Görlach, A.
- Affiliations
- Deutsches Herzzentrum München (DE)
- University of Kaiserslautern (DE)
- Corresponding author
- Görlach, Agnes
- Venue
- Antioxidants & Redox Signaling
- Publisher
- SAGE Publications
- Published
- 2010-08-15
- Volume
- 13
- Issue
- 4
- Pages
- 425-436
- ISSN
- 1523-0864 (ISSN-L)
- 1557-7716
- OpenAlex
- W2036748771
- Cited by
- 92
- References
- 7
- Citations by year
- 2026: 5 · 2024: 4 · 2023: 5 · 2022: 7 · 2021: 3 · 2020: 3 · 2019: 7 · 2018: 10 · 2017: 5 · 2016: 5 · 2015: 10 · 2014: 5 · 2013: 7 · 2012: 9
- FWCI
- 4.49
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Antioxidants and Redox Signaling (publishedVersion)
- PubMed (publishedVersion)
- mediaTUM (Technical University of Munich) (submittedVersion)
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Pulmonary Hypertension Research and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Health Sciences › Medicine › Physiology › Nitric Oxide and Endothelin Effects
- Keywords
- HIF-2α, NOX4, reactive oxygen species, NADPH oxidase, protein stabilization, von Hippel-Lindau protein, prolyl hydroxylation, thrombin, hydrogen peroxide, plasminogen activator inhibitor-1, pulmonary artery smooth muscle cells, vascular remodeling, smooth muscle cell proliferation, hypoxia
- MeSH terms
- NADPH Oxidase 4, Endothelial PAS Domain-Containing Protein 1, Animals, Ascorbic Acid, Cells, Cultured, Humans, Hydrogen Peroxide, Iron, Thrombin, Blotting, Western, Reactive Oxygen Species, Oxidative Stress, NADPH Oxidases, Cell Line, Tumor, Cell Proliferation, Rats, Basic Helix-Loop-Helix Proteins, Von Hippel-Lindau Tumor Suppressor Protein
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