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Hyperglycemia regul...
Hyperglycemia regulates hypoxia-inducible factor-1alpha protein stability and function
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- Catrina, SB (författare)
- Karolinska Institutet
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Okamoto, K (författare)
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- Pereira, T (författare)
- Karolinska Institutet
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- Brismar, K (författare)
- Karolinska Institutet
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- Poellinger, L (författare)
- Karolinska Institutet
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(creator_code:org_t)
- American Diabetes Association, 2004
- 2004
- Engelska.
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Ingår i: Diabetes. - : American Diabetes Association. - 0012-1797 .- 1939-327X. ; 53:12, s. 3226-3232
- Relaterad länk:
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http://diabetes.diab...
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http://kipublication...
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https://doi.org/10.2...
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Abstract
Ämnesord
Stäng
- 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.
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- art (ämneskategori)
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Diabetes
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