PT  - JOURNAL ARTICLE
AU  - Catrina, Sergiu-Bogdan
AU  - Okamoto, Kensaku
AU  - Pereira, Teresa
AU  - Brismar, Kerstin
AU  - Poellinger, Lorenz
TI  - Hyperglycemia Regulates Hypoxia-Inducible Factor-1α Protein Stability and Function
AID  - 10.2337/diabetes.53.12.3226
DP  - 2004 Dec 01
TA  - Diabetes
PG  - 3226--3232
VI  - 53
IP  - 12
4099  - http://diabetes.diabetesjournals.org/content/53/12/3226.short
4100  - http://diabetes.diabetesjournals.org/content/53/12/3226.full
SO  - Diabetes2004 Dec 01; 53
AB  - 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-1α 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-1α, as assessed by transient hypoxia-inducible reporter gene assay. Regulation of HIF-1α function by hyperglycemia could be mimicked by mannitol, suggesting hyperosmolarity as one critical parameter. The interference of hyperglycemia with hypoxia-dependent stabilization of HIF-1α protein levels was confirmed in vivo, where only very low levels of HIF-1α 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-1α against proteasomal degradation and suggest a mechanism by which diabetes interferes with cellular responses to hypoxia.