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

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• 作者：Chia-Hung Hsieh ; Yu-Jung Lin ; Wei-Ling Chen ; Yen-Chih Huang ; Chi-Wei Chang ; Fu-Chou Cheng ; Ren-Shyan Liu and Woei-Cherng Shyu
• 刊名：The Journal of Pathology
• 出版年：2017
• 出版时间：February 2017
• 年：2017
• 卷：241
• 期：3
• 页码：337-349
• 全文大小：3225K
• ISSN：1096-9896

文摘

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 x_c⁻) 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 x_c⁻ 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 x_c⁻-dependent glutamate outflow and suggest that system x_c⁻ is a promising therapeutic target with an extended therapeutic window in stroke. Copyright