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Experiments using proteasomal and prolyl hydroxylases inhibitors indicate that hyperglycemia inhibits hypoxia-induced stabilization of HIF-1\u03b1 protein levels against degradation and suggest that mechanisms in addition to proline hydroxylation may be involved. This effect of hyperglycemia was dose dependent and correlates with a lower transcription activation potency of HIF-1\u03b1, as assessed by transient hypoxia-inducible reporter gene assay. Regulation of HIF-1\u03b1 function by hyperglycemia could be mimicked by mannitol, suggesting hyperosmolarity as one critical parameter. The interference of hyperglycemia with hypoxia-dependent stabilization of HIF-1\u03b1 protein levels was confirmed in vivo, where only very low levels of HIF-1\u03b1 protein could be detected in diabetic wounds, as compared with chronic venous ulcers. In conclusion, our data demonstrate that hyperglycemia impairs hypoxia-dependent protection of HIF-1\u03b1 against proteasomal degradation and suggest a mechanism by which diabetes interferes with cellular responses to hypoxia.<\/jats:p>","DOI":"10.2337\/diabetes.53.12.3226","type":"journal-article","created":{"date-parts":[[2007,3,6]],"date-time":"2007-03-06T14:04:22Z","timestamp":1173189862000},"page":"3226-3232","update-policy":"https:\/\/doi.org\/10.2337\/ada-journal-policies","source":"Crossref","is-referenced-by-count":335,"title":["Hyperglycemia Regulates Hypoxia-Inducible Factor-1\u03b1 Protein Stability and Function"],"prefix":"10.2337","volume":"53","author":[{"given":"Sergiu-Bogdan","family":"Catrina","sequence":"first","affiliation":[{"name":"Department of Molecular Medicine, Karolinska Institutet, Stockholm, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kensaku","family":"Okamoto","sequence":"additional","affiliation":[{"name":"Department of Cellular and Molecular Biology, Medical Nobel Institute, Karolinska Institutet, Stockholm, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Teresa","family":"Pereira","sequence":"additional","affiliation":[{"name":"Department of Cellular and Molecular Biology, Medical Nobel Institute, Karolinska Institutet, Stockholm, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kerstin","family":"Brismar","sequence":"additional","affiliation":[{"name":"Department of Molecular Medicine, Karolinska Institutet, Stockholm, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lorenz","family":"Poellinger","sequence":"additional","affiliation":[{"name":"Department of Cellular and Molecular Biology, Medical Nobel Institute, Karolinska Institutet, Stockholm, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1167","reference":[{"key":"2022031208523189000_R1","doi-asserted-by":"crossref","unstructured":"The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. 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