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    Differential Effects of HIF-1 Inhibition by YC-1 on the Overall Outcome and Blood-Brain Barrier Damage in a Rat Model of Ischemic Stroke

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    Issue Date
    2011-11-16
    Author
    Yan, Jingqi
    Zhou, Bo
    Taheri, Saeid
    Shi, Honglian
    Publisher
    Public Library of Science
    Type
    Article
    Article Version
    Scholarly/refereed, publisher version
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    Abstract
    Hypoxia-inducible factor 1 (HIF-1) is a master regulator of cellular adaptation to hypoxia and has been suggested as a potent therapeutic target in cerebral ischemia. Here we show in an ischemic stroke model of rats that inhibiting HIF-1 and its downstream genes by 3-(5’-hydroxymethyl-2’-furyl)-1-benzylindazole (YC-1) significantly increases mortality and enlarges infarct volume evaluated by MRI and histological staining. Interestingly, the HIF-1 inhibition remarkably ameliorates ischemia-induced blood-brain barrier (BBB) disruption determined by Evans blue leakage although it does not affect brain edema. The result demonstrates that HIF-1 inhibition has differential effects on ischemic outcomes and BBB permeability. It indicates that HIF-1 may have different functions in different brain cells. Further analyses show that ischemia upregulates HIF-1 and its downstream genes erythropoietin (EPO), vascular endothelial growth factor (VEGF), and glucose transporter (Glut) in neurons and brain endothelial cells and that YC-1 inhibits their expression. We postulate that HIF-1-induced VEGF increases BBB permeability while certain other proteins coded by HIF-1’s downstream genes such as epo and glut provide neuroprotection in an ischemic brain. The results indicate that YC-1 lacks the potential as a cerebral ischemic treatment although it confers certain protection to the cerebral vascular system.
    Description
    This is the publisher's version, also available from http://dx.doi.org/10.1371/journal.pone.0027798.
    URI
    http://hdl.handle.net/1808/9285
    DOI
    https://doi.org/10.1371/journal.pone.0027798
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    • Pharmacy Scholarly Works [286]
    Citation
    Yan J, Zhou B, Taheri S, and Shi H. Differential effects of HIF-1 inhibition by YC-1 on the overall outcome and blood brain-barrier damage in a rat model of ischemic stroke. PLoS One 6(11): e27798; 2011. http://dx.doi.org/10.1371/journal.pone.0027798

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    KU Libraries
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    785-864-8983

    KU Libraries
    1425 Jayhawk Blvd
    Lawrence, KS 66045
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    Contact KU ScholarWorks
    785-864-8983
    KU Libraries
    1425 Jayhawk Blvd
    Lawrence, KS 66045
    785-864-8983

    KU Libraries
    1425 Jayhawk Blvd
    Lawrence, KS 66045
    Image Credits
     

     

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