{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,9]],"date-time":"2026-04-09T12:00:25Z","timestamp":1775736025589,"version":"3.50.1"},"reference-count":38,"publisher":"Proceedings of the National Academy of Sciences","issue":"49","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2008,12,9]]},"abstract":"<jats:p>\n            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) 1\u03b1 is the critical transcription factor that regulates adaptive responses to hypoxia. HIF-1\u03b1 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-1\u03b1 stability and activation, resulting in suppression of expression of HIF-1 target genes essential for wound healing both\n            <jats:italic>in vitro<\/jats:italic>\n            and\n            <jats:italic>in vivo<\/jats:italic>\n            . However, by blocking HIF-1\u03b1 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-1\u03b1 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-1\u03b1 is essential for the development of diabetic wounds, and we provide evidence that stabilization of HIF-1\u03b1 is critical to reverse the pathological process.\n          <\/jats:p>","DOI":"10.1073\/pnas.0805230105","type":"journal-article","created":{"date-parts":[[2008,12,5]],"date-time":"2008-12-05T02:49:31Z","timestamp":1228445371000},"page":"19426-19431","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":466,"title":["Stabilization of HIF-1\u03b1 is critical to improve wound healing in diabetic mice"],"prefix":"10.1073","volume":"105","author":[{"given":"Ileana Ruxandra","family":"Botusan","sequence":"first","affiliation":[{"name":"Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden;"},{"name":"Department of Endocrinology, University of Medicine and Pharmacy \u201cCarol Davila\u201d, Bucharest, Romania;"}]},{"given":"Vivekananda Gupta","family":"Sunkari","sequence":"additional","affiliation":[{"name":"Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden;"}]},{"given":"Octavian","family":"Savu","sequence":"additional","affiliation":[{"name":"Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden;"},{"name":"National Institute for Diabetes \u201cC. Paulescu\u201d, Bucharest, Romania;"}]},{"given":"Anca Irinel","family":"Catrina","sequence":"additional","affiliation":[{"name":"Department of Rheumatology, Karolinska Institutet, Karolinska University Hospital, Solna, Sweden;"}]},{"given":"Jacob","family":"Gr\u00fcnler","sequence":"additional","affiliation":[{"name":"Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden;"}]},{"given":"Stina","family":"Lindberg","sequence":"additional","affiliation":[{"name":"Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden;"}]},{"given":"Teresa","family":"Pereira","sequence":"additional","affiliation":[{"name":"Department of Cellular and Molecular Biology, Medical Nobel Institute, Karolinska Institutet, Stockholm, Sweden; and"}]},{"given":"Seppo","family":"Yl\u00e4-Herttuala","sequence":"additional","affiliation":[{"name":"Department of Biotechnology and Molecular Medicine, A. I. Virtanen Institute for Molecular Sciences, University of Kuopio, Finland"}]},{"given":"Lorenz","family":"Poellinger","sequence":"additional","affiliation":[{"name":"Department of Cellular and Molecular Biology, Medical Nobel Institute, Karolinska Institutet, Stockholm, Sweden; and"}]},{"given":"Kerstin","family":"Brismar","sequence":"additional","affiliation":[{"name":"Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden;"}]},{"given":"Sergiu-Bogdan","family":"Catrina","sequence":"additional","affiliation":[{"name":"Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden;"}]}],"member":"341","published-online":{"date-parts":[[2008,12,9]]},"reference":[{"key":"e_1_3_3_1_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(05)67698-2"},{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1529-8019.2006.00093.x"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1002\/dmrr.458"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00268-003-7400-2"},{"key":"e_1_3_3_5_2","first-page":"262","article-title":"Regulation of wound-healing angiogenesis-effect of oxygen gradients and inspired oxygen concentration","volume":"90","author":"Knighton DR","year":"1981","unstructured":"DR Knighton, IA Silver, TK Hunt, Regulation of wound-healing angiogenesis-effect of oxygen gradients and inspired oxygen concentration. 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