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However, its roles in glutamatergic transmission and excitotoxicity are unclear. Here, we proposed that <jats:styled-content style=\"fixed-case\">HIF<\/jats:styled-content>\u20101\u03b1 might contribute to glutamate\u2010mediated excitotoxicity during cerebral ischaemia\u2013reperfusion (<jats:styled-content style=\"fixed-case\">CIR<\/jats:styled-content>) and investigated its molecular mechanism. We showed that an <jats:styled-content style=\"fixed-case\">HIF<\/jats:styled-content>\u20101\u03b1 conditional knockout mouse displayed an inhibition in <jats:styled-content style=\"fixed-case\">CIR<\/jats:styled-content>\u2010induced elevation of extracellular glutamate and <jats:italic>N<\/jats:italic>\u2010methyl\u2010<jats:sc>d<\/jats:sc>\u2010aspartate receptor (<jats:styled-content style=\"fixed-case\">NMDAR<\/jats:styled-content>) activation. By gene screening for glutamate transporters in cortical cells, we found that <jats:styled-content style=\"fixed-case\">HIF<\/jats:styled-content>\u20101\u03b1 mainly regulates the cystine\u2013glutamate transporter (system x<jats:sub>c<\/jats:sub><jats:sup>\u2212<\/jats:sup>) subunit <jats:styled-content style=\"fixed-case\">xCT<\/jats:styled-content> by directly binding to its promoter; <jats:styled-content style=\"fixed-case\">xCT<\/jats:styled-content> and its function are up\u2010regulated in the ischaemic brains of rodents and humans, and the effects lasted for several days. Genetic deletion of <jats:styled-content style=\"fixed-case\">xCT<\/jats:styled-content> in cortical cells of mice inhibits either oxygen glucose deprivation\/reoxygenation (<jats:styled-content style=\"fixed-case\">OGDR<\/jats:styled-content>) or <jats:styled-content style=\"fixed-case\">CIR<\/jats:styled-content>\u2010mediated glutamate excitotoxicity <jats:italic>in vitro<\/jats:italic> and <jats:italic>in vivo<\/jats:italic>. Pharmaceutical inhibition of system x<jats:sub>c<\/jats:sub><jats:sup>\u2212<\/jats:sup> by a clinically approved anti\u2010cancer drug, sorafenib, improves infarct volume and functional outcome in rodents with <jats:styled-content style=\"fixed-case\">CIR<\/jats:styled-content> and its therapeutic window is at least 3 days. Taken together, these findings reveal that <jats:styled-content style=\"fixed-case\">HIF<\/jats:styled-content>\u20101\u03b1 plays a role in <jats:styled-content style=\"fixed-case\">CIR<\/jats:styled-content>\u2010induced glutamate excitotoxicity via the long\u2010lasting activation of system x<jats:sub>c<\/jats:sub><jats:sup>\u2212<\/jats:sup>\u2010dependent glutamate outflow and suggest that system x<jats:sub>c<\/jats:sub><jats:sup>\u2212<\/jats:sup> is a promising therapeutic target with an extended therapeutic window in stroke. Copyright \u00a9 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley &amp; Sons, Ltd.<\/jats:p>","DOI":"10.1002\/path.4838","type":"journal-article","created":{"date-parts":[[2016,11,1]],"date-time":"2016-11-01T08:16:58Z","timestamp":1477988218000},"page":"337-349","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":66,"title":["<scp>HIF<\/scp>\u20101\u03b1 triggers long\u2010lasting glutamate excitotoxicity via system x<sub>c<\/sub><sup>\u2212<\/sup> in cerebral ischaemia\u2013reperfusion"],"prefix":"10.1002","volume":"241","author":[{"given":"Chia\u2010Hung","family":"Hsieh","sequence":"first","affiliation":[{"name":"Graduate Institute of Basic Medical Science China Medical University  No 91, Hsueh\u2010Shih Road Taichung Taiwan 40402"},{"name":"Department of Medical Research China Medical University Hospital  No 2, Yuh\u2010Der Road Taichung Taiwan 40402"},{"name":"Aging Medicine Program China Medical University  No 91, Hsueh\u2010Shih Road Taichung Taiwan 40402"},{"name":"Department of Biomedical Informatics Asia University  No 500, Lioufeng Road Taichung Taiwan 41354"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu\u2010Jung","family":"Lin","sequence":"additional","affiliation":[{"name":"Graduate Institute of Basic Medical Science China Medical University  No 91, Hsueh\u2010Shih Road Taichung Taiwan 40402"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei\u2010Ling","family":"Chen","sequence":"additional","affiliation":[{"name":"Aging Medicine Program China Medical University  No 91, Hsueh\u2010Shih Road Taichung Taiwan 40402"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yen\u2010Chih","family":"Huang","sequence":"additional","affiliation":[{"name":"Graduate Institute of Immunology China Medical University  No 91, Hsueh\u2010Shih Road Taichung Taiwan 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