Hypoxia-inducible factor 1 contributes to N-acetylcysteine’s protection in stroke
dc.contributor.author | Zhang, Ziyan | |
dc.contributor.author | Yan, Jingqi | |
dc.contributor.author | Liu, Ke Jian | |
dc.contributor.author | Shi, Honglian | |
dc.date.accessioned | 2017-03-09T21:34:25Z | |
dc.date.available | 2017-03-09T21:34:25Z | |
dc.date.issued | 2015-03-01 | |
dc.identifier.citation | Zhang, Ziyan, Jingqi Yan, Saeid Taheri, Ke Jian Liu, and Honglian Shi. "Hypoxia-inducible Factor 1 Contributes to N-acetylcysteineâ s Protection in Stroke." Free Radical Biology and Medicine 68 (2014): 8-21. | en_US |
dc.identifier.uri | http://hdl.handle.net/1808/23390 | |
dc.description.abstract | Stroke is a leading cause of adult morbidity and mortality with very limited treatment options. Evidence from preclinical models of ischemic stroke has demonstrated that the antioxidant N-acetylcysteine (NAC) effectively protects the brain from ischemic injury. Here, we evaluated a new pathway through which NAC exerted its neuroprotection in a transient cerebral ischemia animal model. Our results demonstrated that pretreatment with NAC increased protein levels of hypoxia-inducible factor-1α (HIF-1α), the regulatable subunit of HIF-1, and its target proteins erythropoietin (EPO) and glucose transporter (GLUT)-3, in the ipsilateral hemispheres of rodents subjected to 90 min middle cerebral artery occlusion (MCAO) and 24 h reperfusion. Interestingly, after NAC pretreatment and stroke, the contralateral hemisphere also demonstrated increased levels of HIF-1α, EPO, and GLUT-3, but to a lesser extent. Suppressing HIF-1 activity with two widely used pharmacological inhibitors, YC-1 and 2ME2, and specific knockout of neuronal HIF-1α abolished NAC’s neuroprotective effects. The results also showed that YC-1 and 2ME2 massively enlarged infarcts, indicating that their toxic effect was larger than just abolishing NAC’s neuroprotective effects. Furthermore, we determined the mechanism of NAC-mediated HIF-1α induction. We observed that NAC pretreatment upregulated heat-shock protein 90 (Hsp90) expression and increased the interaction of Hsp90 with HIF-1α in ischemic brains. The enhanced association of Hsp90 with HIF-1α increased HIF-1α stability. Moreover, Hsp90 inhibition attenuated NAC-induced HIF-1α protein accumulation and diminished NAC-induced neuroprotection in the MCAO model. These results strongly indicate that HIF-1 plays an important role in NAC-mediated neuroprotection and provide a new molecular mechanism involved in the antioxidant’s neuroprotection in ischemic stroke. | en_US |
dc.publisher | Elsevier | en_US |
dc.rights | This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License 3.0 (CC BY-NC-ND 3.0 US), which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made. | en_US |
dc.rights.uri | http://creativecommons.org/licenses/by-nc-nd/3.0/ | |
dc.subject | HIF-1 | en_US |
dc.subject | Hsp90 | en_US |
dc.subject | NAC | en_US |
dc.subject | Neuroprotection | en_US |
dc.subject | Stroke | en_US |
dc.subject | Free radicals | en_US |
dc.title | Hypoxia-inducible factor 1 contributes to N-acetylcysteine’s protection in stroke | en_US |
dc.type | Article | en_US |
kusw.kuauthor | Shi, Honglian | |
kusw.kudepartment | Pharmacology & Toxicology | en_US |
dc.identifier.doi | 10.1016/j.freeradbiomed.2013.11.007 | en_US |
kusw.oaversion | Scholarly/refereed, author accepted manuscript | en_US |
kusw.oapolicy | This item meets KU Open Access policy criteria. | en_US |
dc.rights.accessrights | openAccess |
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Except where otherwise noted, this item's license is described as: This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License 3.0 (CC BY-NC-ND 3.0 US), which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.