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

Jingqi Yan, Bo Zhou, Saeid Taheri, Honglian Shi

Research output: Contribution to journalArticle

50 Citations (Scopus)

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.

Original languageEnglish (US)
Article numbere27798
JournalPLoS One
Volume6
Issue number11
DOIs
StatePublished - Nov 16 2011
Externally publishedYes

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Hypoxia-Inducible Factor 1
blood-brain barrier
Blood-Brain Barrier
stroke
Rats
animal models
Stroke
Brain
ischemia
brain
vascular endothelial growth factors
Genes
Vascular Endothelial Growth Factor A
Permeability
permeability
Ischemia
erythropoietin
Evans Blue
glucose transporters
genes

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

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.

In: PLoS One, Vol. 6, No. 11, e27798, 16.11.2011.

Research output: Contribution to journalArticle

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