PMID- 15561954
OWN - NLM
STAT- MEDLINE
DCOM- 20050414
LR  - 20220408
IS  - 0012-1797 (Print)
IS  - 0012-1797 (Linking)
VI  - 53
IP  - 12
DP  - 2004 Dec
TI  - Hyperglycemia regulates hypoxia-inducible factor-1alpha protein stability and 
      function.
PG  - 3226-32
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-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.
FAU - Catrina, Sergiu-Bogdan
AU  - Catrina SB
AD  - Department of Molecular Medicine, Karolinska Institutet, Stockholm, Sweden. 
      sergiu-bogdan.catrina@molmed.ki.se
FAU - Okamoto, Kensaku
AU  - Okamoto K
FAU - Pereira, Teresa
AU  - Pereira T
FAU - Brismar, Kerstin
AU  - Brismar K
FAU - Poellinger, Lorenz
AU  - Poellinger L
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Diabetes
JT  - Diabetes
JID - 0372763
RN  - 0 (HIF1A protein, human)
RN  - 0 (Hypoxia-Inducible Factor 1, alpha Subunit)
RN  - 0 (Transcription Factors)
RN  - 3OWL53L36A (Mannitol)
RN  - IY9XDZ35W2 (Glucose)
SB  - IM
MH  - Cell Hypoxia
MH  - Cells, Cultured
MH  - Endothelium, Vascular/physiology
MH  - Fibroblasts/physiology
MH  - Gene Expression Regulation/drug effects
MH  - Glucose/*pharmacology
MH  - Humans
MH  - Hyperglycemia/*physiopathology
MH  - Hypoxia-Inducible Factor 1, alpha Subunit
MH  - Mannitol/pharmacology
MH  - Microcirculation
MH  - Skin/blood supply
MH  - Transcription Factors/genetics/*physiology
EDAT- 2004/11/25 09:00
MHDA- 2005/04/15 09:00
CRDT- 2004/11/25 09:00
PHST- 2004/11/25 09:00 [pubmed]
PHST- 2005/04/15 09:00 [medline]
PHST- 2004/11/25 09:00 [entrez]
AID - 53/12/3226 [pii]
AID - 10.2337/diabetes.53.12.3226 [doi]
PST - ppublish
SO  - Diabetes. 2004 Dec;53(12):3226-32. doi: 10.2337/diabetes.53.12.3226.