Hypoxia-inducible factor-1α contributes to brain edema after stroke by regulating aquaporins and glycerol distribution in brain.

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  • Additional Information
    • Source:
      Publisher: Bentham Science Publishers Country of Publication: United Arab Emirates NLM ID: 101208439 Publication Model: Print Cited Medium: Internet ISSN: 1875-5739 (Electronic) Linking ISSN: 15672026 NLM ISO Abbreviation: Curr Neurovasc Res Subsets: MEDLINE
    • Publication Information:
      Original Publication: Saif Zone, Sharjah, U.A.E. ; San Francisco, CA : Bentham Science Publishers, c2004-
    • Subject Terms:
      Aquaporin 4/*metabolism ; Aquaporins/*metabolism ; Brain/*metabolism ; Brain Edema/*metabolism ; Glycerol/*metabolism ; Hypoxia-Inducible Factor 1, alpha Subunit/*physiology ; Infarction, Middle Cerebral Artery/*metabolism ; Signal Transduction/*physiology; Animals ; Aquaporin 4/antagonists & inhibitors ; Aquaporin 4/physiology ; Aquaporins/antagonists & inhibitors ; Aquaporins/physiology ; Brain/blood supply ; Brain Edema/etiology ; Hypoxia-Inducible Factor 1, alpha Subunit/antagonists & inhibitors ; Infarction, Middle Cerebral Artery/complications ; Male ; Rats ; Rats, Sprague-Dawley ; Reperfusion Injury/complications ; Reperfusion Injury/metabolism
    • Abstract:
      Brain edema following stroke is a critical clinical problem due to its association with increased morbidity and mortality. Despite its significance, present treatment for brain edema simply provides symptomatic relief due to the fact that molecular mechanisms underlying brain edema remain poorly understood. The present study investigated the role of hypoxia-inducible factor-1α (HIF-1α) and aquaporins (AQP-4 and -9) in regulating cerebral glycerol accumulation and inducing brain edema in a rodent model of stroke. Two-hours of middle cerebral artery occlusion (MCAO) followed by reperfusion was performed in male Sprague-Dawley rats (250-280 g). Anti-AQP-4 antibody, anti-AQP-9 antibody, or 2-Methoxyestradiol (2ME2, an inhibitor of HIF-1α) was given at the time of MCAO. The rats were sacrificed at 1 and 24 hours after reperfusion and their brains were examined. Extracellular and intracellular glycerol concentration of brain tissue was calculated with an enzymatic glycerol assay. The protein expressions of HIF-1α, AQP-4 and AQP-9 were determined by Western blotting. Brain edema was measured by brain water content. Compared to control, edema (p < 0.01), increased glycerol (p < 0.05), and enhanced expressions of HIF-1α, AQP-4, and AQP-9 (p < 0.05) were observed after stroke. With inhibition of AQP-4, AQP-9 or HIF-1α, edema and extracellular glycerol were significantly (p < 0.01) decreased while intracellular glycerol was increased (p < 0.01) 1 hour after stroke. Inhibition of HIF-1α with 2ME2 suppressed (p < 0.01) the expression of AQP-4 and AQP-9. These findings suggest that HIF-1α serves as an upstream regulator of cerebral glycerol concentrations and brain edema via a molecular pathway involving AQP-4 and AQP-9. Pharmacological blockade of this pathway in stroke patients may provide novel therapeutic strategies.
    • Accession Number:
      0 (Aqp4 protein, rat)
      0 (Aqp9 protein, rat)
      0 (Aquaporin 4)
      0 (Aquaporins)
      0 (Hif1a protein, rat)
      0 (Hypoxia-Inducible Factor 1, alpha Subunit)
      PDC6A3C0OX (Glycerol)
    • Publication Date:
      Date Created: 20110107 Date Completed: 20120112 Latest Revision: 20191111
    • Publication Date:
      20221213
    • Accession Number:
      10.2174/156720211794520251
    • Accession Number:
      21208160