PMID- 21617913
OWN - NLM
STAT- MEDLINE
DCOM- 20120221
LR  - 20220330
IS  - 1420-9071 (Electronic)
IS  - 1420-682X (Linking)
VI  - 69
IP  - 1
DP  - 2012 Jan
TI  - HIF-1 is involved in high glucose-induced paracellular permeability of brain 
      endothelial cells.
PG  - 115-28
LID - 10.1007/s00018-011-0731-5 [doi]
AB  - Experimental evidence from human patients and animal models of diabetes has 
      demonstrated that hyperglycemia increases blood-brain barrier (BBB) permeability, 
      which is associated with increased risk of neurological dysfunction. However, the 
      mechanism underlying high glucose-induced BBB disruption is not understood. Here 
      we investigated the role of hypoxia-inducible factor-1 (HIF-1) in high 
      glucose-induced endothelial permeability in vitro using mouse brain microvascular 
      endothelial cells (b.End3). Our results demonstrated that high glucose (30 mM) 
      upregulated the protein level of HIF-1alpha, the regulatable subunit of HIF-1, and 
      increased the transcriptional activity of HIF-1 in the endothelial cells. At the 
      same time, high glucose increased the paracellular permeability associated with 
      diminished expression and disrupted continuity of tight junction proteins 
      occludin and zona occludens protein-1 (ZO-1) of the endothelial cells. 
      Upregulating HIF-1 activity by cobalt chloride increased the paracellular 
      permeability of the endothelial cells exposed to normal glucose (5.5 mM). In 
      contrast, downregulating HIF-1 activity by HIF-1alpha inhibitors and HIF-1alpha specific 
      siRNA ameliorated the increased paracellular permeability and the alterations of 
      distribution pattern of occludin and ZO-1 induced by high glucose. In addition, 
      high glucose increased expression of vascular endothelial growth factor (VEGF), a 
      downstream gene of HIF-1. Inhibiting VEGF improved the expression pattern of 
      occludin and ZO-1, and attenuated the endothelial leakage. Furthermore, key 
      results were confirmed in human brain microvascular endothelial cells. These 
      results strongly indicate that HIF-1 plays an important role in high 
      glucose-induced BBB dysfunction. The results will help us understand the 
      molecular mechanisms involved in hyperglycemia-induced BBB dysfunction and 
      neurological outcomes.
FAU - Yan, Jingqi
AU  - Yan J
AD  - Department of Pharmacology and Toxicology, School of Pharmacy, University of 
      Kansas, Lawrence, KS 66045, USA.
FAU - Zhang, Ziyan
AU  - Zhang Z
FAU - Shi, Honglian
AU  - Shi H
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20110527
PL  - Switzerland
TA  - Cell Mol Life Sci
JT  - Cellular and molecular life sciences : CMLS
JID - 9705402
RN  - 0 (Hypoxia-Inducible Factor 1, alpha Subunit)
RN  - 0 (Indazoles)
RN  - 0 (Membrane Proteins)
RN  - 0 (OCLN protein, human)
RN  - 0 (Occludin)
RN  - 0 (Ocln protein, mouse)
RN  - 0 (Phosphoproteins)
RN  - 0 (TJP1 protein, human)
RN  - 0 (Tjp1 protein, mouse)
RN  - 0 (Vascular Endothelial Growth Factor A)
RN  - 0 (Zonula Occludens-1 Protein)
RN  - 154453-18-6 (3-(5'-hydroxymethyl-2'-furyl)-1-benzylindazole)
RN  - 4TI98Z838E (Estradiol)
RN  - 6I2QW73SR5 (2-Methoxyestradiol)
RN  - IY9XDZ35W2 (Glucose)
SB  - IM
MH  - 2-Methoxyestradiol
MH  - Animals
MH  - *Blood-Brain Barrier/metabolism/physiopathology
MH  - Brain/metabolism
MH  - Endothelial Cells/metabolism
MH  - Estradiol/analogs & derivatives/pharmacology
MH  - Glucose/*metabolism
MH  - Humans
MH  - Hyperglycemia/metabolism/*physiopathology
MH  - Hypoxia-Inducible Factor 1, alpha Subunit/antagonists & inhibitors/*metabolism
MH  - Indazoles/pharmacology
MH  - Membrane Proteins/metabolism
MH  - Mice
MH  - Occludin
MH  - Permeability
MH  - Phosphoproteins/metabolism
MH  - Tight Junctions/metabolism
MH  - Vascular Endothelial Growth Factor A/antagonists & inhibitors/*metabolism
MH  - Zonula Occludens-1 Protein
EDAT- 2011/05/28 06:00
MHDA- 2012/02/22 06:00
CRDT- 2011/05/28 06:00
PHST- 2011/01/18 00:00 [received]
PHST- 2011/05/09 00:00 [accepted]
PHST- 2011/04/22 00:00 [revised]
PHST- 2011/05/28 06:00 [entrez]
PHST- 2011/05/28 06:00 [pubmed]
PHST- 2012/02/22 06:00 [medline]
AID - 10.1007/s00018-011-0731-5 [doi]
PST - ppublish
SO  - Cell Mol Life Sci. 2012 Jan;69(1):115-28. doi: 10.1007/s00018-011-0731-5. Epub 
      2011 May 27.