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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

Yan, Jingqi
; 
Zhou, Bo
; 
Taheri, Saeid
; 
Shi, Honglian
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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.
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This is the publisher's version, also available from http://dx.doi.org/10.1371/journal.pone.0027798.
Date
2011-11-16
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Public Library of Science
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Pharmacy Scholarly Works
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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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https://hdl.handle.net/1808/9285
DOI
10.1371/journal.pone.0027798
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