Hyperglycentia regulates hypoxia-inducible factor-1α protein stability and function

被引:313
作者
Catrina, SB
Okamoto, K
Pereira, T
Brismar, K
Poellinger, L
机构
[1] Karolinska Inst, Dept Mol Med, Stockholm, Sweden
[2] Karolinska Inst, Med Nobel Inst, Dept Cellular & Mol Biol, Stockholm, Sweden
关键词
D O I
10.2337/diabetes.53.12.3226
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
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-1a 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.
引用
收藏
页码:3226 / 3232
页数:7
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