Evidence that collaboration between HIF-1a and Notch-1 promotes neuronal cell death in ischemic stroke

Yi-Lin Cheng, Jong-Sung Park, Silvia Manzanero, Yuri Choi, Sang-Ha Baik, Eitan Okun, Mathias Gelderblom, David Yang-Wei Fann, Tim Magnus, Bradley S Launikonis, Mark P Mattson, Christopher G Sobey, Dong-Gyu Jo, Thiruma Arumugam

Research output: Contribution to journalArticleResearchpeer-review

Abstract

Recent findings suggest that Notch-1 signaling contributes to neuronal death in ischemic stroke, but the underlying mechanisms are unknown. Hypoxia inducible factor-1alpha (HIF-1alpha), a global regulator of cellular responses to hypoxia, can interact with Notch and modulate its signaling during hypoxic stress. Here we show that Notch signaling interacts with the HIF-1alpha pathway in the process of ischemic neuronal death. We found that a chemical inhibitor of the Notch-activating enzyme, gamma-secretase, and a HIF-1alpha inhibitor, protect cultured cortical neurons against ischemic stress, and combined inhibition of Notch-1 and HIF-1alpha further decreased neuronal death. HIF-1alpha and Notch intracellular domain (NICD) are co-expressed in the neuronal nucleus, and co-immunoprecipitated in cultured neurons and in brain tissue from mice subjected to focal ischemic stroke. Overexpression of NICD and HIF-1alpha in cultured human neural cells enhanced cell death under ischemia-like conditions, and a HIF-1alpha inhibitor rescued the cells. RNA interference-mediated depletion of endogenous NICD and HIF-1alpha also decreased cell death under ischemia-like conditions. Finally, mice treated with inhibitors of gamma-secretase and HIF-1alpha exhibited improved outcome after focal ischemic stroke, with combined treatment being superior to individual treatments. Additional findings suggest that the NICD and HIF-1alpha collaborate to engage pro-inflammatory and apoptotic signaling pathways in stroke.
Original languageEnglish
Pages (from-to)286 - 295
Number of pages10
JournalNeurobiology of Disease
Volume62
DOIs
Publication statusPublished - 2014

Cite this

Cheng, Y-L., Park, J-S., Manzanero, S., Choi, Y., Baik, S-H., Okun, E., ... Arumugam, T. (2014). Evidence that collaboration between HIF-1a and Notch-1 promotes neuronal cell death in ischemic stroke. Neurobiology of Disease, 62, 286 - 295. https://doi.org/10.1016/j.nbd.2013.10.009
Cheng, Yi-Lin ; Park, Jong-Sung ; Manzanero, Silvia ; Choi, Yuri ; Baik, Sang-Ha ; Okun, Eitan ; Gelderblom, Mathias ; Fann, David Yang-Wei ; Magnus, Tim ; Launikonis, Bradley S ; Mattson, Mark P ; Sobey, Christopher G ; Jo, Dong-Gyu ; Arumugam, Thiruma. / Evidence that collaboration between HIF-1a and Notch-1 promotes neuronal cell death in ischemic stroke. In: Neurobiology of Disease. 2014 ; Vol. 62. pp. 286 - 295.
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title = "Evidence that collaboration between HIF-1a and Notch-1 promotes neuronal cell death in ischemic stroke",
abstract = "Recent findings suggest that Notch-1 signaling contributes to neuronal death in ischemic stroke, but the underlying mechanisms are unknown. Hypoxia inducible factor-1alpha (HIF-1alpha), a global regulator of cellular responses to hypoxia, can interact with Notch and modulate its signaling during hypoxic stress. Here we show that Notch signaling interacts with the HIF-1alpha pathway in the process of ischemic neuronal death. We found that a chemical inhibitor of the Notch-activating enzyme, gamma-secretase, and a HIF-1alpha inhibitor, protect cultured cortical neurons against ischemic stress, and combined inhibition of Notch-1 and HIF-1alpha further decreased neuronal death. HIF-1alpha and Notch intracellular domain (NICD) are co-expressed in the neuronal nucleus, and co-immunoprecipitated in cultured neurons and in brain tissue from mice subjected to focal ischemic stroke. Overexpression of NICD and HIF-1alpha in cultured human neural cells enhanced cell death under ischemia-like conditions, and a HIF-1alpha inhibitor rescued the cells. RNA interference-mediated depletion of endogenous NICD and HIF-1alpha also decreased cell death under ischemia-like conditions. Finally, mice treated with inhibitors of gamma-secretase and HIF-1alpha exhibited improved outcome after focal ischemic stroke, with combined treatment being superior to individual treatments. Additional findings suggest that the NICD and HIF-1alpha collaborate to engage pro-inflammatory and apoptotic signaling pathways in stroke.",
author = "Yi-Lin Cheng and Jong-Sung Park and Silvia Manzanero and Yuri Choi and Sang-Ha Baik and Eitan Okun and Mathias Gelderblom and Fann, {David Yang-Wei} and Tim Magnus and Launikonis, {Bradley S} and Mattson, {Mark P} and Sobey, {Christopher G} and Dong-Gyu Jo and Thiruma Arumugam",
year = "2014",
doi = "10.1016/j.nbd.2013.10.009",
language = "English",
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pages = "286 -- 295",
journal = "Neurobiology of Disease",
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Cheng, Y-L, Park, J-S, Manzanero, S, Choi, Y, Baik, S-H, Okun, E, Gelderblom, M, Fann, DY-W, Magnus, T, Launikonis, BS, Mattson, MP, Sobey, CG, Jo, D-G & Arumugam, T 2014, 'Evidence that collaboration between HIF-1a and Notch-1 promotes neuronal cell death in ischemic stroke' Neurobiology of Disease, vol. 62, pp. 286 - 295. https://doi.org/10.1016/j.nbd.2013.10.009

Evidence that collaboration between HIF-1a and Notch-1 promotes neuronal cell death in ischemic stroke. / Cheng, Yi-Lin; Park, Jong-Sung; Manzanero, Silvia; Choi, Yuri; Baik, Sang-Ha; Okun, Eitan; Gelderblom, Mathias; Fann, David Yang-Wei; Magnus, Tim; Launikonis, Bradley S; Mattson, Mark P; Sobey, Christopher G; Jo, Dong-Gyu; Arumugam, Thiruma.

In: Neurobiology of Disease, Vol. 62, 2014, p. 286 - 295.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Evidence that collaboration between HIF-1a and Notch-1 promotes neuronal cell death in ischemic stroke

AU - Cheng, Yi-Lin

AU - Park, Jong-Sung

AU - Manzanero, Silvia

AU - Choi, Yuri

AU - Baik, Sang-Ha

AU - Okun, Eitan

AU - Gelderblom, Mathias

AU - Fann, David Yang-Wei

AU - Magnus, Tim

AU - Launikonis, Bradley S

AU - Mattson, Mark P

AU - Sobey, Christopher G

AU - Jo, Dong-Gyu

AU - Arumugam, Thiruma

PY - 2014

Y1 - 2014

N2 - Recent findings suggest that Notch-1 signaling contributes to neuronal death in ischemic stroke, but the underlying mechanisms are unknown. Hypoxia inducible factor-1alpha (HIF-1alpha), a global regulator of cellular responses to hypoxia, can interact with Notch and modulate its signaling during hypoxic stress. Here we show that Notch signaling interacts with the HIF-1alpha pathway in the process of ischemic neuronal death. We found that a chemical inhibitor of the Notch-activating enzyme, gamma-secretase, and a HIF-1alpha inhibitor, protect cultured cortical neurons against ischemic stress, and combined inhibition of Notch-1 and HIF-1alpha further decreased neuronal death. HIF-1alpha and Notch intracellular domain (NICD) are co-expressed in the neuronal nucleus, and co-immunoprecipitated in cultured neurons and in brain tissue from mice subjected to focal ischemic stroke. Overexpression of NICD and HIF-1alpha in cultured human neural cells enhanced cell death under ischemia-like conditions, and a HIF-1alpha inhibitor rescued the cells. RNA interference-mediated depletion of endogenous NICD and HIF-1alpha also decreased cell death under ischemia-like conditions. Finally, mice treated with inhibitors of gamma-secretase and HIF-1alpha exhibited improved outcome after focal ischemic stroke, with combined treatment being superior to individual treatments. Additional findings suggest that the NICD and HIF-1alpha collaborate to engage pro-inflammatory and apoptotic signaling pathways in stroke.

AB - Recent findings suggest that Notch-1 signaling contributes to neuronal death in ischemic stroke, but the underlying mechanisms are unknown. Hypoxia inducible factor-1alpha (HIF-1alpha), a global regulator of cellular responses to hypoxia, can interact with Notch and modulate its signaling during hypoxic stress. Here we show that Notch signaling interacts with the HIF-1alpha pathway in the process of ischemic neuronal death. We found that a chemical inhibitor of the Notch-activating enzyme, gamma-secretase, and a HIF-1alpha inhibitor, protect cultured cortical neurons against ischemic stress, and combined inhibition of Notch-1 and HIF-1alpha further decreased neuronal death. HIF-1alpha and Notch intracellular domain (NICD) are co-expressed in the neuronal nucleus, and co-immunoprecipitated in cultured neurons and in brain tissue from mice subjected to focal ischemic stroke. Overexpression of NICD and HIF-1alpha in cultured human neural cells enhanced cell death under ischemia-like conditions, and a HIF-1alpha inhibitor rescued the cells. RNA interference-mediated depletion of endogenous NICD and HIF-1alpha also decreased cell death under ischemia-like conditions. Finally, mice treated with inhibitors of gamma-secretase and HIF-1alpha exhibited improved outcome after focal ischemic stroke, with combined treatment being superior to individual treatments. Additional findings suggest that the NICD and HIF-1alpha collaborate to engage pro-inflammatory and apoptotic signaling pathways in stroke.

UR - http://www.sciencedirect.com/science/article/pii/S0969996113002842

U2 - 10.1016/j.nbd.2013.10.009

DO - 10.1016/j.nbd.2013.10.009

M3 - Article

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SP - 286

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JO - Neurobiology of Disease

JF - Neurobiology of Disease

SN - 0969-9961

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