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Hoffmann, R. A wiki for the life sciences where authorship matters. Nature Genetics (2008)

Hyperglycemia regulates hypoxia-inducible factor-1alpha protein stability and function.

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.[1]


  1. Hyperglycemia regulates hypoxia-inducible factor-1alpha protein stability and function. Catrina, S.B., Okamoto, K., Pereira, T., Brismar, K., Poellinger, L. Diabetes (2004) [Pubmed]
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