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

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.

journal_name

Curr Neurovasc Res

journal_title

Current neurovascular research

authors

Higashida T,Peng C,Li J,Dornbos D 3rd,Teng K,Li X,Kinni H,Guthikonda M,Ding Y

doi

10.2174/156720211794520251

subject

Has Abstract

pub_date

2011-02-01 00:00:00

pages

44-51

issue

eissn

1567-2026

issn

1875-5739

pii

BSP/CNR/E-Pub/00040

journal_volume

pub_type

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