Evidence that collaboration between HIF-1alpha 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 and Arumugam, Thiruma V. (2014) Evidence that collaboration between HIF-1alpha and Notch-1 promotes neuronal cell death in ischemic stroke. Neurobiology of Disease, 62 286-295. doi:10.1016/j.nbd.2013.10.009

Author 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 V.
Title Evidence that collaboration between HIF-1alpha and Notch-1 promotes neuronal cell death in ischemic stroke
Formatted title
Evidence that collaboration between HIF-1α and Notch-1 promotes neuronal cell death in ischemic stroke
Journal name Neurobiology of Disease   Check publisher's open access policy
ISSN 0969-9961
Publication date 2014-02-01
Year available 2013
Sub-type Article (original research)
DOI 10.1016/j.nbd.2013.10.009
Volume 62
Start page 286
End page 295
Total pages 10
Place of publication Maryland Heights, MO, United States
Publisher Academic Press
Collection year 2014
Language eng
Formatted abstract
• Hypoxia inducible factor-1α (HIF-1α) can modulate Notch signaling.
• Notch-HIF-1α signaling contributes to ischemic neuronal death.
• Agents that target Notch-HIF-1α may prove effective stroke therapy.

Recent findings suggest that Notch-1 signaling contributes to neuronal death in ischemic stroke, but the underlying mechanisms are unknown. Hypoxia inducible factor-1α (HIF-1α), 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-1α pathway in the process of ischemic neuronal death. We found that a chemical inhibitor of the Notch-activating enzyme, γ-secretase, and a HIF-1α inhibitor, protect cultured cortical neurons against ischemic stress, and combined inhibition of Notch-1 and HIF-1α further decreased neuronal death. HIF-1α 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-1α in cultured human neural cells enhanced cell death under ischemia-like conditions, and a HIF-1α inhibitor rescued the cells. RNA interference-mediated depletion of endogenous NICD and HIF-1α also decreased cell death under ischemia-like conditions. Finally, mice treated with inhibitors of γ-secretase and HIF-1α exhibited improved outcome after focal ischemic stroke, with combined treatment being superior to individual treatments. Additional findings suggest that the NICD and HIF-1α collaborate to engage pro-inflammatory and apoptotic signaling pathways in stroke.
Keyword Apoptosis
Ischemic stroke
Neuronal cell death
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ
Additional Notes Available online 16 October 2013

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2014 Collection
School of Biomedical Sciences Publications
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Citation counts: TR Web of Science Citation Count  Cited 16 times in Thomson Reuters Web of Science Article | Citations
Scopus Citation Count Cited 17 times in Scopus Article | Citations
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Created: Fri, 29 Nov 2013, 03:13:54 EST by Dr Thiruma V Arumugam on behalf of School of Biomedical Sciences