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Diabetes 53:3226-3232, 2004
© 2004 by the American Diabetes Association, Inc.

Hyperglycemia Regulates Hypoxia-Inducible Factor-1{alpha} Protein Stability and Function

Sergiu-Bogdan Catrina1, Kensaku Okamoto2, Teresa Pereira2, Kerstin Brismar1, and Lorenz Poellinger2

1 Department of Molecular Medicine, Karolinska Institutet, Stockholm, Sweden
2 Department of Cellular and Molecular Biology, Medical Nobel Institute, Karolinska Institutet, Stockholm, Sweden

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-1{alpha} 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{alpha}, as assessed by transient hypoxia-inducible reporter gene assay. Regulation of HIF-1{alpha} 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{alpha} protein levels was confirmed in vivo, where only very low levels of HIF-1{alpha} 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{alpha} against proteasomal degradation and suggest a mechanism by which diabetes interferes with cellular responses to hypoxia.

Address correspondencereprint requests to Sergiu-Bogdan Catrina, MD, PhD, Department of Molecular Medicine, Karolinska Hospital M1:O2, Stockholm, S-171776, Sweden. E-mail: sergiu-bogdan.catrina{at}molmed.ki.se


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Copyright © 2004 by the American Diabetes Association.