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

The DOI matches its Crossref record; 39 of the 39 references it cites were found in a registry or an index.

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

Open access
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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Crossref · 10.1073/pnas.0805230105

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Metadata

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
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
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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