Evidence that collaboration between HIF-1α 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 V. Arumugam

Research output: Contribution to journalArticlepeer-review

78 Scopus citations


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.

Original languageEnglish
Pages (from-to)286-295
Number of pages10
JournalNeurobiology of Disease
StatePublished - Feb 2014

Bibliographical note

Funding Information:
This research was supported by the National Research Foundation of Korea grants ( 2012R1A2A2A01047551 & 2012R1A1A2009093 ), a grant of the Korea Healthcare technology R&D project ( A092042 ) from the Korean Government, a grant by the National Heart Foundation of Australia for a Grant-In-Aid ( G 09B 4272 ), an Australian National Health and Medical Research Council grant ( NHMRC APP1008048 ), an Australian Research Council Future Fellowship to TVA ( ARCFT100100427 ) and an Intramural Research Program of the National Institute on Aging .


  • Apoptosis
  • HIF-1α
  • Ischemic stroke
  • Neuronal cell death
  • Notch


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