title: Hyperglycemia regulates hypoxia-inducible factor-1alpha protein stability and function.
abstract: Hyperglycemia and hypoxia are suggested to play essential pathophysiological roles in the complications of diabetes, which may result from a defective response of the tissues to low oxygen tension. In this study, we show that in primary dermal fibroblasts and endothelial cells, hyperglycemia interferes with the function of hypoxia-inducible factor-1 (HIF-1), a transcription factor that is essential for adaptive responses of the cell to hypoxia. Experiments using proteasomal and prolyl hydroxylases inhibitors indicate that hyperglycemia inhibits hypoxia-induced stabilization of HIF-1alpha 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-1alpha, as assessed by transient hypoxia-inducible reporter gene assay. Regulation of HIF-1alpha function by hyperglycemia could be mimicked by mannitol, suggesting hyperosmolarity as one critical parameter. The interference of hyperglycemia with hypoxia-dependent stabilization of HIF-1alpha protein levels was confirmed in vivo, where only very low levels of HIF-1alpha 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-1alpha against proteasomal degradation and suggest a mechanism by which diabetes interferes with cellular responses to hypoxia.
authors.affiliation: Department of Molecular Medicine, Karolinska Institutet, Stockholm, Sweden. sergiu-bogdan.catrina@molmed.ki.se
authors.forename: Sergiu-Bogdan
authors.initials: SB
authors.lastname: Catrina
authors.forename: Kensaku
authors.initials: K
authors.lastname: Okamoto
authors.forename: Teresa
authors.initials: T
authors.lastname: Pereira
authors.forename: Kerstin
authors.initials: K
authors.lastname: Brismar
authors.forename: Lorenz
authors.initials: L
authors.lastname: Poellinger
mesh_terms: D015687:Cell Hypoxia; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000502:physiology; D005347:Fibroblasts / Q000502:physiology; D005786:Gene Expression Regulation / Q000187:drug effects; D005947:Glucose / Q000494:pharmacology*; D006801:Humans; D006943:Hyperglycemia / Q000503:physiopathology*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008353:Mannitol / Q000494:pharmacology; D008833:Microcirculation; D012867:Skin / Q000098:blood supply; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology*
chemical_list: C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D014157:Transcription Factors; D008353:Mannitol; D005947:Glucose