ArticleProceedings of the National Academy of Sciences of the United States of America2016
Glutathione adducts induced by ischemia and deletion of glutaredoxin-1 stabilize HIF-1α and improve limb revascularization.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 48 papers, 1 of them a synthesis that pooled it.
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Who cites it
48 citing papers in PubMed, 1 synthesis or guideline pooled it, 86 citations in OpenAlex.
- Involvement of heat shock proteins HSP70 in the mechanisms of endogenous neuroprotection: the prospect of using HSP70 modulators.Frontiers in cellular neuroscience · 2023Pooled it
- Interaction of PEGylated gold nanorods with HIF-1α/Ki-67 in inhibiting immunosuppression and arresting cancer proliferation in murine fibrosarcoma.Scientific reports · 2026Article
- Role of hypoxia-inducible factor - 1 alpha on the progression of cervical intraepithelial neoplasia and cervical cancer: a narrative review.Frontiers in oncology · 2026Review
- Low hypoxia tolerance as a determinant of the proinflammatory phenotype: a trained immunity perspective.Frontiers in immunology · 2026Review
- Review
- Hyperbaric Oxygen Therapy Improved Neovascularisation Following Limb Ischaemia-The Role of ROS Mitigation.Journal of cellular and molecular medicine · 2024Article
- Glutaredoxin-1 modulates the NF-κB signaling pathway to activate inducible nitric oxide synthase in experimental necrotizing enterocolitis.Molecular therapy. Methods & clinical development · 2024Article
- Hypoxia, oxidative stress, and the interplay of HIFs and NRF2 signaling in cancer.Experimental & molecular medicine · 2024Review
- Targeting Hypoxia-Inducible Factor-1 (HIF-1) in Cancer: Emerging Therapeutic Strategies and Pathway Regulation.Pharmaceuticals (Basel, Switzerland) · 2024Review
- Chitosan Particles Complexed with CA5-HIF-1α Plasmids Increase Angiogenesis and Improve Wound Healing.International journal of molecular sciences · 2023Article
- Gbb glutathionylation promotes its proteasome-mediated degradation to inhibit synapse growth.The Journal of cell biology · 2023Article
- Article
- CARD9 deficiency improves the recovery of limb ischemia in mice with ambient fine particulate matter exposure.Frontiers in cardiovascular medicine · 2023Article
- Hypoxia Affects the Antioxidant Activity of Glutaredoxin 3 inAntioxidants (Basel, Switzerland) · 2022Article
- HIF1, HSF1, and NRF2: Oxidant-Responsive Trio Raising Cellular Defenses and Engaging Immune System.Chemical research in toxicology · 2022Review
- Endothelial PPARδ facilitates the post-ischemic vascular repair through interaction with HIF1α.Theranostics · 2022Article
- Oxidized GAPDH transfers S-glutathionylation to a nuclear protein Sirtuin-1 leading to apoptosis.Free radical biology & medicine · 2021Article
- Is Biochemical Follow Up Possible in Peripheral Arterial Disease Treatment: Hypoxia Inducible Factor-1 Alpha?Vascular specialist international · 2021Article
- Glutathionylation chemistry promotes interleukin-1 beta-mediated glycolytic reprogramming and pro-inflammatory signaling in lung epithelial cells.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2021Article
- Strategies to Overcome the Barrier of Ischemic Microenvironment in Cell Therapy of Cardiovascular Disease.International journal of molecular sciences · 2021Review
Corrections and comments
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Authors and funding
7 authors at 1 institution in 1 country.
Funding
Abstract
Reactive oxygen species (ROS) are increased in ischemic tissues and necessary for revascularization; however, the mechanism remains unclear. Exposure of cysteine residues to ROS in the presence of glutathione (GSH) generates GSH-protein adducts that are specifically reversed by the cytosolic thioltransferase, glutaredoxin-1 (Glrx). Here, we show that a key angiogenic transcriptional factor hypoxia-inducible factor (HIF)-1α is stabilized by GSH adducts, and the genetic deletion of Glrx improves ischemic revascularization. In mouse muscle C2C12 cells, HIF-1α protein levels are increased by increasing GSH adducts with cell-permeable oxidized GSH (GSSG-ethyl ester) or 2-acetylamino-3-[4-(2-acetylamino-2-carboxyethylsulfanyl thiocarbonylamino) phenylthiocarbamoylsulfanyl] propionic acid (2-AAPA), an inhibitor of glutathione reductase. A biotin switch assay shows that GSSG-ester-induced HIF-1α contains reversibly modified thiols, and MS confirms GSH adducts on Cys(520) (mouse Cys(533)). In addition, an HIF-1α Cys(520) serine mutant is resistant to 2-AAPA-induced HIF-1α stabilization. Furthermore, Glrx overexpression prevents HIF-1α stabilization, whereas Glrx ablation by siRNA increases HIF-1α protein and expression of downstream angiogenic genes. Blood flow recovery after femoral artery ligation is significantly improved in Glrx KO mice, associated with increased levels of GSH-protein adducts, capillary density, vascular endothelial growth factor (VEGF)-A, and HIF-1α in the ischemic muscles. Therefore, Glrx ablation stabilizes HIF-1α by increasing GSH adducts on Cys(520) promoting in vivo HIF-1α stabilization, VEGF-A production, and revascularization in the ischemic muscles.
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