HIF-1α triggers long-lasting glutamate excitotoxicity via system xc- in cerebral ischaemia-reperfusion

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Title:	HIF-1α triggers long-lasting glutamate excitotoxicity via system xc- in cerebral ischaemia-reperfusion
Authors:	謝佳宏;Hsieh, Chia-Hung;*;Lin, Yu-Jung;Lin, Yu-Jung;Che, Wei-Ling;Chen, Wei-Ling;Hua, Yen-Chih;Huang, Yen-Chih;Chan, Chi-Wei;Chang, Chi-Wei;Chen, Fu-Chou;Cheng, Fu-Chou;Li, Ren-Shyan;Liu, Ren-Shyan;Woei-Cherng;Shyu, Woei-Cherng
Contributors:	生物資訊與醫學工程學系
Date:	2016-11
Issue Date:	2017-03-01 05:45:26 (UTC+0)
Abstract:	Hypoxia-inducible factor 1α (HIF-1α) controls many genes involved in physiological and pathological processes. However, its roles in glutamatergic transmission and excitotoxicity are unclear. Here, we proposed that HIF-1α might contribute to glutamate-mediated excitotoxicity during cerebral ischaemia–reperfusion (CIR) and investigated its molecular mechanism. We showed that an HIF-1α conditional knockout mouse displayed an inhibition in CIR-induced elevation of extracellular glutamate and N-methyl-d-aspartate receptor (NMDAR) activation. By gene screening for glutamate transporters in cortical cells, we found that HIF-1α mainly regulates the cystine–glutamate transporter (system xc−) subunit xCT by directly binding to its promoter; xCT and its function are up-regulated in the ischaemic brains of rodents and humans, and the effects lasted for several days. Genetic deletion of xCT in cortical cells of mice inhibits either oxygen glucose deprivation/reoxygenation (OGDR) or CIR-mediated glutamate excitotoxicity in vitro and in vivo. Pharmaceutical inhibition of system xc− by a clinically approved anti-cancer drug, sorafenib, improves infarct volume and functional outcome in rodents with CIR and its therapeutic window is at least 3 days. Taken together, these findings reveal that HIF-1α plays a role in CIR-induced glutamate excitotoxicity via the long-lasting activation of system xc−-dependent glutamate outflow and suggest that system xc− is a promising therapeutic target with an extended therapeutic window in stroke. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
Relation:	JOURNAL OF PATHOLOGY
Appears in Collections:	[Department of Biomedical informatics ] Journal Article

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