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Hypoxia-inducible factor-1 alpha is involved in RIP-induced necroptosis caused by in vitro and in vivo ischemic brain injury

Necroptosis, a novel type of programmed cell death, is involved in stroke-induced ischemic brain injury. Although studies have sought to explore the mechanisms of necroptosis, its signaling pathway has not yet to be completely elucidated. Thus, we used oxygen-glucose deprivation (OGD) and middle cer...

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Autores principales: Yang, Xiao-Sa, Yi, Tai-Long, Zhang, Sai, Xu, Zhong-Wei, Yu, Ze-Qi, Sun, Hong-Tao, Yang, Cheng, Tu, Yue, Cheng, Shi-Xiang
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5517428/
https://www.ncbi.nlm.nih.gov/pubmed/28724891
http://dx.doi.org/10.1038/s41598-017-06088-0
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author Yang, Xiao-Sa
Yi, Tai-Long
Zhang, Sai
Xu, Zhong-Wei
Yu, Ze-Qi
Sun, Hong-Tao
Yang, Cheng
Tu, Yue
Cheng, Shi-Xiang
author_facet Yang, Xiao-Sa
Yi, Tai-Long
Zhang, Sai
Xu, Zhong-Wei
Yu, Ze-Qi
Sun, Hong-Tao
Yang, Cheng
Tu, Yue
Cheng, Shi-Xiang
author_sort Yang, Xiao-Sa
collection PubMed
description Necroptosis, a novel type of programmed cell death, is involved in stroke-induced ischemic brain injury. Although studies have sought to explore the mechanisms of necroptosis, its signaling pathway has not yet to be completely elucidated. Thus, we used oxygen-glucose deprivation (OGD) and middle cerebral artery occlusion (MCAO) models mimicking ischemic stroke (IS) conditions to investigate mechanisms of necroptosis. We found that OGD and MCAO induced cell death, local brain ischemia and neurological deficit, while zVAD-fmk (zVAD, an apoptotic inhibitor), GSK’872 (a receptor interacting protein kinase-3 (RIP3) inhibitor), and combined treatment alleviated cell death and ischemic brain injury. Moreover, OGD and MCAO upregulated protein expression of the triggers of necroptosis: receptor interacting protein kinase-1 (RIP1), RIP3 and mixed lineage kinase domain-like protein (MLKL). The upregulation of these proteins was inhibited by GSK’872, combination treatments and RIP3 siRNA but not zVAD treatment. Intriguingly, hypoxia-inducible factor-1 alpha (HIF-1α), an important transcriptional factor under hypoxic conditions, was upregulated by OGD and MCAO. Similar to their inhibitory effects on aforementioned proteins upregulation, GSK’872, combination treatments and RIP3 siRNA decreased HIF-1α protein level. These findings indicate that necroptosis contributes to ischemic brain injury induced by OGD and MCAO and implicate HIF-1α, RIP1, RIP3, and MLKL in necroptosis.
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spelling pubmed-55174282017-07-20 Hypoxia-inducible factor-1 alpha is involved in RIP-induced necroptosis caused by in vitro and in vivo ischemic brain injury Yang, Xiao-Sa Yi, Tai-Long Zhang, Sai Xu, Zhong-Wei Yu, Ze-Qi Sun, Hong-Tao Yang, Cheng Tu, Yue Cheng, Shi-Xiang Sci Rep Article Necroptosis, a novel type of programmed cell death, is involved in stroke-induced ischemic brain injury. Although studies have sought to explore the mechanisms of necroptosis, its signaling pathway has not yet to be completely elucidated. Thus, we used oxygen-glucose deprivation (OGD) and middle cerebral artery occlusion (MCAO) models mimicking ischemic stroke (IS) conditions to investigate mechanisms of necroptosis. We found that OGD and MCAO induced cell death, local brain ischemia and neurological deficit, while zVAD-fmk (zVAD, an apoptotic inhibitor), GSK’872 (a receptor interacting protein kinase-3 (RIP3) inhibitor), and combined treatment alleviated cell death and ischemic brain injury. Moreover, OGD and MCAO upregulated protein expression of the triggers of necroptosis: receptor interacting protein kinase-1 (RIP1), RIP3 and mixed lineage kinase domain-like protein (MLKL). The upregulation of these proteins was inhibited by GSK’872, combination treatments and RIP3 siRNA but not zVAD treatment. Intriguingly, hypoxia-inducible factor-1 alpha (HIF-1α), an important transcriptional factor under hypoxic conditions, was upregulated by OGD and MCAO. Similar to their inhibitory effects on aforementioned proteins upregulation, GSK’872, combination treatments and RIP3 siRNA decreased HIF-1α protein level. These findings indicate that necroptosis contributes to ischemic brain injury induced by OGD and MCAO and implicate HIF-1α, RIP1, RIP3, and MLKL in necroptosis. Nature Publishing Group UK 2017-07-19 /pmc/articles/PMC5517428/ /pubmed/28724891 http://dx.doi.org/10.1038/s41598-017-06088-0 Text en © The Author(s) 2017 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Yang, Xiao-Sa
Yi, Tai-Long
Zhang, Sai
Xu, Zhong-Wei
Yu, Ze-Qi
Sun, Hong-Tao
Yang, Cheng
Tu, Yue
Cheng, Shi-Xiang
Hypoxia-inducible factor-1 alpha is involved in RIP-induced necroptosis caused by in vitro and in vivo ischemic brain injury
title Hypoxia-inducible factor-1 alpha is involved in RIP-induced necroptosis caused by in vitro and in vivo ischemic brain injury
title_full Hypoxia-inducible factor-1 alpha is involved in RIP-induced necroptosis caused by in vitro and in vivo ischemic brain injury
title_fullStr Hypoxia-inducible factor-1 alpha is involved in RIP-induced necroptosis caused by in vitro and in vivo ischemic brain injury
title_full_unstemmed Hypoxia-inducible factor-1 alpha is involved in RIP-induced necroptosis caused by in vitro and in vivo ischemic brain injury
title_short Hypoxia-inducible factor-1 alpha is involved in RIP-induced necroptosis caused by in vitro and in vivo ischemic brain injury
title_sort hypoxia-inducible factor-1 alpha is involved in rip-induced necroptosis caused by in vitro and in vivo ischemic brain injury
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5517428/
https://www.ncbi.nlm.nih.gov/pubmed/28724891
http://dx.doi.org/10.1038/s41598-017-06088-0
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