title: 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.affiliation: Department of Physiology, Yong Loo Lin School Medicine, National University of Singapore, 117597, Singapore; School of Biomedical Sciences, The University of Queensland, St Lucia, QLD 4072, Australia.
authors.forename: Yi-Lin
authors.initials: YL
authors.lastname: Cheng
authors.affiliation: School of Pharmacy, Sungkyunkwan University, Suwon 440-746, Republic of Korea.
authors.forename: Jong-Sung
authors.initials: JS
authors.lastname: Park
authors.affiliation: School of Biomedical Sciences, The University of Queensland, St Lucia, QLD 4072, Australia.
authors.forename: Silvia
authors.initials: S
authors.lastname: Manzanero
authors.affiliation: School of Pharmacy, Sungkyunkwan University, Suwon 440-746, Republic of Korea.
authors.forename: Yuri
authors.initials: Y
authors.lastname: Choi
authors.affiliation: School of Pharmacy, Sungkyunkwan University, Suwon 440-746, Republic of Korea.
authors.forename: Sang-Ha
authors.initials: SH
authors.lastname: Baik
authors.affiliation: The Leslie and Susan Gonda Multidisciplinary Brain Research Center, The Mina and Everard Goodman Faculty of Life Sciences, Bar Ilan University, Ramat Gan, Israel.
authors.forename: Eitan
authors.initials: E
authors.lastname: Okun
authors.affiliation: Department of Neurology, University Clinic Hamburg-Eppendorf, Martinistr, 52, D-20246 Hamburg, Germany.
authors.forename: Mathias
authors.initials: M
authors.lastname: Gelderblom
authors.affiliation: School of Biomedical Sciences, The University of Queensland, St Lucia, QLD 4072, Australia.
authors.forename: David Yang-Wei
authors.initials: DY
authors.lastname: Fann
authors.affiliation: Department of Neurology, University Clinic Hamburg-Eppendorf, Martinistr, 52, D-20246 Hamburg, Germany.
authors.forename: Tim
authors.initials: T
authors.lastname: Magnus
authors.affiliation: School of Biomedical Sciences, The University of Queensland, St Lucia, QLD 4072, Australia.
authors.forename: Bradley S
authors.initials: BS
authors.lastname: Launikonis
authors.affiliation: Laboratory of Neurosciences, National Institute on Aging Intramural Research Program, Baltimore, MD, USA; Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: Mark P
authors.initials: MP
authors.lastname: Mattson
authors.affiliation: Department of Pharmacology, Monash University, Clayton, Victoria 3800, Australia.
authors.forename: Christopher G
authors.initials: CG
authors.lastname: Sobey
authors.affiliation: School of Pharmacy, Sungkyunkwan University, Suwon 440-746, Republic of Korea. Electronic address: jodg@skku.edu.
authors.forename: Dong-Gyu
authors.initials: DG
authors.lastname: Jo
authors.affiliation: Department of Physiology, Yong Loo Lin School Medicine, National University of Singapore, 117597, Singapore; School of Biomedical Sciences, The University of Queensland, St Lucia, QLD 4072, Australia; School of Pharmacy, Sungkyunkwan University, Suwon 440-746, Republic of Korea. Electronic address: phstva@nus.edu.sg.
authors.forename: Thiruma V
authors.initials: TV
authors.lastname: Arumugam
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism; D000818:Animals; D002545:Brain Ischemia / Q000378:metabolism*; D016923:Cell Death / Q000502:physiology; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D020243:Infarction, Anterior Cerebral Artery / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000378:metabolism*; D051881:Receptor, Notch1 / Q000378:metabolism*; D015427:Reperfusion Injury / Q000378:metabolism; D020521:Stroke / Q000378:metabolism*
chemical_list: C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C497762:Notch1 protein, mouse; D051881:Receptor, Notch1; D053829:Amyloid Precursor Protein Secretases
keywords: Apoptosis; HIF-1α; Ischemic stroke; Neuronal cell death; Notch