Evidence that collaboration between HIF-1α 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-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.

• 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)
• Copyright: © 2013.

Chemical References

• Hif1a protein, mouse
• Hypoxia-Inducible Factor 1, alpha Subunit
• Notch1 protein, mouse
• Receptor, Notch1
• Amyloid Precursor Protein Secretases

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)