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

Hypoxia-inducible factor 1 (HIF-1) controls many genes involved in physiological and pathological processes. However, its roles in glutamatergic transmission and excitotoxicity are unclear. Here, we proposed that HIF-1 might contribute to glutamate-mediated excitotoxicity during cerebral ischaemia-reperfusion (CIR) and investigated its molecular mechanism. We showed that an HIF-1 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-1 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-1 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 (c) 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.