title: HIF-1α triggers long-lasting glutamate excitotoxicity via system xc-in cerebral ischaemia-reperfusion.
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.
authors: Graduate Institute of Basic Medical Science, China Medical University, No 91, Hsueh-Shih Road, Taichung, Taiwan, 40402.|Department of Medical Research, China Medical University Hospital, No 2, Yuh-Der Road, Taichung, Taiwan, 40402.|Aging Medicine Program, China Medical University, No 91, Hsueh-Shih Road, Taichung, Taiwan, 40402.|Department of Biomedical Informatics, Asia University, No 500, Lioufeng Road, Taichung, Taiwan, 41354.
authors: Chia-Hung
authors: CH
authors: Hsieh
authors: Graduate Institute of Basic Medical Science, China Medical University, No 91, Hsueh-Shih Road, Taichung, Taiwan, 40402.
authors: Yu-Jung
authors: YJ
authors: Lin
authors: Aging Medicine Program, China Medical University, No 91, Hsueh-Shih Road, Taichung, Taiwan, 40402.
authors: Wei-Ling
authors: WL
authors: Chen
authors: Graduate Institute of Immunology, China Medical University, No 91, Hsueh-Shih Road, Taichung, Taiwan, 40402.
authors: Yen-Chih
authors: YC
authors: Huang
authors: National PET/Cyclotron Center and Department of Nuclear Medicine, Taipei Veterans General Hospital, No 201, Shipai Road, Taipei, Taiwan, 11217.
authors: Chi-Wei
authors: CW
authors: Chang
authors: Stem Cell Center, Department of Medical Research, Taichung Veterans General Hospital, 1650 Taiwan Boulevard Section 4, Taichung, Taiwan, 40705.
authors: Fu-Chou
authors: FC
authors: Cheng
authors: National PET/Cyclotron Center and Department of Nuclear Medicine, Taipei Veterans General Hospital, No 201, Shipai Road, Taipei, Taiwan, 11217.
authors: Ren-Shyan
authors: RS
authors: Liu
authors: Department of Neurology, Center for Neuropsychiatry, China Medical University and Hospital, No 91, Hsueh-Shih Road, Taichung, Taiwan, 40402.
authors: Woei-Cherng
authors: WC
authors: Shyu
mesh_terms: D027182:Amino Acid Transport System y+ / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000378:metabolism*; D002545:Brain Ischemia / Q000378:metabolism*; D015687:Cell Hypoxia / Q000502:physiology*; D002469:Cell Separation / Q000379:methods; D018698:Glutamic Acid / Q000378:metabolism; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D051379:Mice; D015533:Transcriptional Activation / Q000502:physiology; D015854:Up-Regulation
chemical_list: D027182:Amino Acid Transport System y+; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C492255:Slc7a11 protein, mouse; D018698:Glutamic Acid
keywords: N-methyl-d-aspartate receptor; cerebral ischaemia-reperfusion; hypoxia-inducible factor 1α; sorafenib; system xc−