TY - JOUR
T1 - Evidence that collaboration between HIF-1α and Notch-1 promotes neuronal cell death in ischemic stroke
AU - Cheng, Yi Lin
AU - Park, Jong Sung
AU - Manzanero, Silvia
AU - Choi, Yuri
AU - Baik, Sang Ha
AU - Okun, Eitan
AU - Gelderblom, Mathias
AU - Fann, David Yang Wei
AU - Magnus, Tim
AU - Launikonis, Bradley S.
AU - Mattson, Mark P.
AU - Sobey, Christopher G.
AU - Jo, Dong Gyu
AU - Arumugam, Thiruma V.
PY - 2014
Y1 - 2014
N2 - 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.
AB - 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.
KW - Apoptosis
KW - HIF-1α
KW - Ischemic stroke
KW - Neuronal cell death
KW - Notch
UR - http://www.scopus.com/inward/record.url?scp=84887143993&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84887143993&partnerID=8YFLogxK
U2 - 10.1016/j.nbd.2013.10.009
DO - 10.1016/j.nbd.2013.10.009
M3 - Article
C2 - 24141018
AN - SCOPUS:84887143993
SN - 0969-9961
VL - 62
SP - 286
EP - 295
JO - Neurobiology of Disease
JF - Neurobiology of Disease
ER -