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
Open Access Status DOI
Volume 62
Start page 286
End page 295
Total pages 10
Place of publication Maryland Heights, MO, United States
Publisher Academic Press
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 21 times in Thomson Reuters Web of Science Article | Citations
Scopus Citation Count Cited 22 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