Evidence that collaboration between HIF-1伪 and Notch-1 promotes neuronal cell death in ischemic stroke

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• 作者：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
• 关键词：Apoptosis ; HIF-1伪 ; Ischemic stroke ; Neuronal cell death ; Notch
• 刊名：Neurobiology of Disease
• 出版年：February, 2014
• 年：2014
• 卷：62
• 期：Complete
• 页码：286-295
• 全文大小：1669 K

文摘

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