| First Author | Hsieh CH | Year | 2017 |
| Journal | J Pathol | Volume | 241 |
| Issue | 3 | Pages | 337-349 |
| PubMed ID | 27801527 | Mgi Jnum | J:241725 |
| Mgi Id | MGI:5903552 | Doi | 10.1002/path.4838 |
| Citation | Hsieh CH, et al. (2017) HIF-1alpha triggers long-lasting glutamate excitotoxicity via system xc- in cerebral ischaemia-reperfusion. J Pathol 241(3):337-349 |
| abstractText | Hypoxia-inducible factor 1alpha (HIF-1alpha) controls many genes involved in physiological and pathological processes. However, its roles in glutamatergic transmission and excitotoxicity are unclear. Here, we proposed that HIF-1alpha might contribute to glutamate-mediated excitotoxicity during cerebral ischaemia-reperfusion (CIR) and investigated its molecular mechanism. We showed that an HIF-1alpha 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-1alpha 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-1alpha 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 (c) 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. |
