PMID- 22540931
OWN - NLM
STAT- MEDLINE
DCOM- 20121019
LR  - 20211021
IS  - 1759-0914 (Electronic)
IS  - 1759-0914 (Linking)
VI  - 4
IP  - 4
DP  - 2012 May 30
TI  - Hypoxia-inducible factor 1 protects hypoxic astrocytes against glutamate 
      toxicity.
PG  - 231-41
LID - 10.1042/AN20120006 [doi]
LID - e00090
AB  - Stroke is a major neurological disorder characterized by an increase in the Glu 
      (glutamate) concentration resulting in excitotoxicity and eventually cellular 
      damage and death in the brain. HIF-1 (hypoxia-inducible factor-1), a 
      transcription factor, plays an important protective role in promoting cellular 
      adaptation to hypoxic conditions. It is known that HIF-1alpha, the regulatable 
      subunit of HIF-1, is expressed by astrocytes under severe ischaemia. However, the 
      effect of HIF-1 on astrocytes following Glu toxicity during ischaemia has not 
      been well studied. We investigated the role of HIF-1 in protecting ischaemic 
      astrocytes against Glu toxicity. Immunostaining with GFAP (glial fibrillary 
      acidic protein) confirmed the morphological modification of astrocytes in the 
      presence of 1 mM Glu under normoxia. Interestingly, when the astrocytes were 
      exposed to severe hypoxia (0.1% O2), the altered cell morphology was ameliorated 
      with up-regulation of HIF-1alpha. To ascertain HIF-1's protective role, effects of 
      two HIF-1alpha inhibitors, YC-1 [3-(50-hydroxymethyl-20-furyl)-1-benzylindazole] and 
      2Me2 (2-methoxyoestradiol), were tested. Both the inhibitors decreased the 
      recovery in astrocyte morphology and increased cell death. Given that ischaemia 
      increases ROS (reactive oxygen species), we examined the role of GSH (reduced 
      glutathione) in the mechanism for this protection. GSH was increased under 
      hypoxia, and this correlated with an increase in HIF-1alpha stabilization in the 
      astrocytes. Furthermore, inhibition of GSH with BSO (l-butathione sulfoximine) 
      decreased HIF-1alpha expression, suggesting its role in the stabilization of HIF-1alpha. 
      Overall, our results indicate that the expression of HIF-1alpha under hypoxia has a 
      protective effect on astrocytes in maintaining cell morphology and viability in 
      response to Glu toxicity.
FAU - Badawi, Yomna
AU  - Badawi Y
AD  - Department of Pharmacology and Toxicology, University of Kansas, Lawrence, KS 
      66045, USA.
FAU - Ramamoorthy, Prabhu
AU  - Ramamoorthy P
FAU - Shi, Honglian
AU  - Shi H
LA  - eng
GR  - R01 NS058807/NS/NINDS NIH HHS/United States
GR  - R01NS058807/NS/NINDS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20120530
PL  - United States
TA  - ASN Neuro
JT  - ASN neuro
JID - 101507115
RN  - 0 (Enzyme Activators)
RN  - 0 (Excitatory Amino Acids)
RN  - 0 (Glial Fibrillary Acidic Protein)
RN  - 0 (Hypoxia-Inducible Factor 1)
RN  - 0 (Hypoxia-Inducible Factor 1, alpha Subunit)
RN  - 0 (Indazoles)
RN  - 154453-18-6 (3-(5'-hydroxymethyl-2'-furyl)-1-benzylindazole)
RN  - 3KX376GY7L (Glutamic Acid)
RN  - 4TI98Z838E (Estradiol)
RN  - 6I2QW73SR5 (2-Methoxyestradiol)
RN  - EC 1.1.1.27 (L-Lactate Dehydrogenase)
RN  - GAN16C9B8O (Glutathione)
SB  - IM
MH  - 2-Methoxyestradiol
MH  - Analysis of Variance
MH  - Animals
MH  - Animals, Newborn
MH  - Astrocytes/*drug effects
MH  - Cell Hypoxia/drug effects
MH  - Cerebral Cortex/cytology
MH  - Cytotoxicity Tests, Immunologic
MH  - Dose-Response Relationship, Drug
MH  - Enzyme Activators/pharmacology
MH  - Estradiol/analogs & derivatives/pharmacology
MH  - Excitatory Amino Acids/*toxicity
MH  - Gene Expression Regulation/drug effects
MH  - Glial Fibrillary Acidic Protein/metabolism
MH  - Glutamic Acid/*toxicity
MH  - Glutathione/metabolism
MH  - Hypoxia-Inducible Factor 1/*pharmacology
MH  - Hypoxia-Inducible Factor 1, alpha Subunit/metabolism
MH  - Indazoles/pharmacology
MH  - L-Lactate Dehydrogenase/metabolism
MH  - Rats
MH  - Rats, Sprague-Dawley
PMC - PMC3363983
EDAT- 2012/05/01 06:00
MHDA- 2012/10/20 06:00
PMCR- 2012/05/30
CRDT- 2012/05/01 06:00
PHST- 2012/05/01 06:00 [entrez]
PHST- 2012/05/01 06:00 [pubmed]
PHST- 2012/10/20 06:00 [medline]
PHST- 2012/05/30 00:00 [pmc-release]
AID - AN20120006 [pii]
AID - e00090 [pii]
AID - 10.1042/AN20120006 [doi]
PST - epublish
SO  - ASN Neuro. 2012 May 30;4(4):231-41. doi: 10.1042/AN20120006.