Cited by 534Wound Healing and TreatmentsCancer, Hypoxia, and MetabolismDiabetic Foot Ulcer Assessment and Management

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Stabilization of HIF-1α is critical to improve wound healing in diabetic mice

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Botusan, Ileana Ruxandra, Sunkari, Vivekananda Gupta, Savu, Octavian, Catrina, Anca Irinel, Grünler, Jacob, Lindberg, Stina, Pereira, Teresa, Ylä-Herttuala, Seppo, Poellinger, Lorenz, Brismar, Kerstin, Catrina, Sergiu-Bogdan·2008·Proceedings of the National Academy of Sciences

DOI 10.1073/pnas.0805230105PMC PMC2614777

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Abstract

Relative hypoxia is essential in wound healing since it normally plays a pivotal role in regulation of all the critical processes involved in tissue repair. Hypoxia-inducible factor (HIF) 1α is the critical transcription factor that regulates adaptive responses to hypoxia. HIF-1α stability and function is regulated by oxygen-dependent soluble hydroxylases targeting critical proline and asparaginyl residues. Here we show that hyperglycemia complexly affects both HIF-1α stability and activation, resulting in suppression of expression of HIF-1 target genes essential for wound healing both in vitro and in vivo . However, by blocking HIF-1α hydroxylation through chemical inhibition, it is possible to reverse this negative effect of hyperglycemia and to improve the wound healing process (i.e., granulation, vascularization, epidermal regeneration, and recruitment of endothelial precursors). Local adenovirus-mediated transfer of two stable HIF constructs demonstrated that stabilization of HIF-1α is necessary and sufficient for promoting wound healing in a diabetic environment. Our findings outline the necessity to develop specific hydroxylase inhibitors as therapeutic agents for chronic diabetes wounds. In conclusion, we demonstrate that impaired regulation of HIF-1α is essential for the development of diabetic wounds, and we provide evidence that stabilization of HIF-1α is critical to reverse the pathological process.

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Authors: Botusan, I. R., Sunkari, V. G., Savu, O., Catrina, A. I., Grünler, J., Lindberg, S., Pereira, T., Ylä-Herttuala, S., Poellinger, L., Brismar, K., & Catrina, S.-B.
Affiliations: Carol Davila University of Medicine and Pharmacy (RO)
Karolinska Institutet (SE)
Karolinska University Hospital (SE)
Department of Biotechnology and Molecular Medicine, A. I. Virtanen Institute for Molecular Sciences, University of Kuopio, Finland
ORCID: Botusan, Ileana Ruxandra
Sunkari, Vivekananda Gupta
Savu, Octavian
Catrina, Anca Irinel
Grünler, Jacob
Pereira, Teresa
Brismar, Kerstin
Catrina, Sergiu-Bogdan
Venue: Proceedings of the National Academy of Sciences
Publisher: National Academy of Sciences
Published: 2008-12-09
Volume: 105
Issue: 49
Pages: 19426-19431
ISSN: 0027-8424 (ISSN-L)
1091-6490
DOI: 10.1073/pnas.0805230105
PMC: PMC2614777
OpenAlex: W2163809998
Cited by: 533
References: 39
Citations by year: 2026: 38 · 2025: 36 · 2024: 35 · 2023: 33 · 2022: 35 · 2021: 38 · 2020: 37 · 2019: 36 · 2018: 30 · 2017: 31 · 2016: 29 · 2015: 27 · 2014: 31 · 2013: 30 · 2012: 21
FWCI: 16.10
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Locations: Proceedings of the National Academy of Sciences (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
Funders: Åke Wiberg Stiftelse
Vetenskapsrådet
Topics: Health Sciences › Medicine › Surgery › Wound Healing and Treatments
Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetic Foot Ulcer Assessment and Management
Keywords: HIF-1α, hypoxia-inducible factor, wound healing, diabetic wounds, hyperglycemia, protein stabilization, chronic wounds, granulation tissue, vascularization, epidermal regeneration, endothelial precursors, adenoviral gene transfer, diabetic mice
MeSH terms: Amino Acids, Dicarboxylic, Animals, Hypoxia, Chronic Disease, Disease Models, Animal, Enzyme Inhibitors, Fibroblasts, Humans, Mixed Function Oxygenases, Hyperglycemia, Kidney Neoplasms, Mice, Inbred C57BL, Mice, Mutant Strains, Wound Healing, Gene Expression, 3T3 Cells, Diabetic Foot, Dermis, Cell Line, Tumor, Mice, Hypoxia-Inducible Factor 1, alpha Subunit

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Stabilization of HIF-1α is critical to improve wound healing in diabetic mice

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