Abstract |
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.
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Authors | 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 |
Journal | Neurobiology of disease
(Neurobiol Dis)
Vol. 62
Pg. 286-95
(Feb 2014)
ISSN: 1095-953X [Electronic] United States |
PMID | 24141018
(Publication Type: Journal Article, Research Support, N.I.H., Intramural, Research Support, Non-U.S. Gov't)
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Copyright | © 2013. |
Chemical References |
- Hif1a protein, mouse
- Hypoxia-Inducible Factor 1, alpha Subunit
- Notch1 protein, mouse
- Receptor, Notch1
- Amyloid Precursor Protein Secretases
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Topics |
- Amyloid Precursor Protein Secretases
(metabolism)
- Animals
- Brain Ischemia
(metabolism)
- Cell Death
(physiology)
- Cell Line, Tumor
- Cells, Cultured
- Humans
- Hypoxia-Inducible Factor 1, alpha Subunit
(metabolism)
- Infarction, Anterior Cerebral Artery
(metabolism)
- Male
- Mice
- Mice, Inbred C57BL
- Neurons
(metabolism)
- Receptor, Notch1
(metabolism)
- Reperfusion Injury
(metabolism)
- Stroke
(metabolism)
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