Abstract
Although hypoxia-inducible factor-1α (HIF-1α) has been extensively studied in brain injury following hypoxia-ischemia, the role of HIF-1α in early brain injury (EBI) after subarachnoid hemorrhage (SAH) remains unclear. The present study was under taken to investigate a potential role of HIF-1α in EBI after SAH. Rats (n=60) were randomly divided into sham+vehicle, SAH+2-methoxyestradiol (2ME2), and SAH+vehicle groups. The SAH model was induced by endovascular perforation and all the rats were subsequently sacrificed at 24h after SAH. We found that treatment with 2ME2 suppressed the expression of HIF-1α, BNIP3 and VEGF and reduced cell apoptosis, blood-brain barrier (BBB) permeability, brain edema, and neurologic scores. Double fluorescence labeling revealed that HIF-1α was expressed predominantly in the nuclei of neurons and TUNEL-positive cells. Our work demonstrated that HIF-1α may play a role in EBI after SAH, causing cell apoptosis, BBB disruption, and brain edema by up-regulating its downstream targets, BNIP3 and VEGF. These effects were blocked by the HIF-1α inhibitor, 2ME2.
Keywords:
2ME2; BNIP3; Early brain injury; Hypoxia-inducible factor-1α; Subarachnoid hemorrhage; VEGF.
Copyright © 2013 Elsevier Inc. All rights reserved.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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2-Methoxyestradiol
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Animals
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Brain Injuries / drug therapy*
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Brain Injuries / etiology*
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Brain Injuries / metabolism
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Disease Models, Animal
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Endovascular Procedures / methods
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Estradiol / administration & dosage
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Estradiol / analogs & derivatives*
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Estradiol / therapeutic use
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Hypoxia-Inducible Factor 1, alpha Subunit / antagonists & inhibitors*
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Hypoxia-Inducible Factor 1, alpha Subunit / physiology
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Male
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Membrane Proteins / antagonists & inhibitors
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Membrane Proteins / biosynthesis
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Mitochondrial Proteins
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Neuroprotective Agents / administration & dosage
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Neuroprotective Agents / therapeutic use
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Proto-Oncogene Proteins / antagonists & inhibitors
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Proto-Oncogene Proteins / biosynthesis
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Rats
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Rats, Sprague-Dawley
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Subarachnoid Hemorrhage / complications*
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Subarachnoid Hemorrhage / drug therapy
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Subarachnoid Hemorrhage / metabolism
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Vascular Endothelial Growth Factor A / antagonists & inhibitors
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Vascular Endothelial Growth Factor A / biosynthesis
Substances
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BNIP3 protein, rat
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Hif1a protein, rat
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Hypoxia-Inducible Factor 1, alpha Subunit
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Membrane Proteins
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Mitochondrial Proteins
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Neuroprotective Agents
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Proto-Oncogene Proteins
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Vascular Endothelial Growth Factor A
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Estradiol
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2-Methoxyestradiol