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Deletion or Inhibition of the Oxygen Sensor PHD1 Protects against Ischemic Stroke via Reprogramming of Neuronal Metabolism.
Quaegebeur, Annelies; Segura, Inmaculada; Schmieder, Roberta; Verdegem, Dries; Decimo, Ilaria; Bifari, Francesco; Dresselaers, Tom; Eelen, Guy; Ghosh, Debapriva; Davidson, Shawn M; Schoors, Sandra; Broekaert, Dorien; Cruys, Bert; Govaerts, Kristof; De Legher, Carla; Bouché, Ann; Schoonjans, Luc; Ramer, Matt S; Hung, Gene; Bossaert, Goele; Cleveland, Don W; Himmelreich, Uwe; Voets, Thomas; Lemmens, Robin; Bennett, C Frank; Robberecht, Wim; De Bock, Katrien; Dewerchin, Mieke; Ghesquière, Bart; Fendt, Sarah-Maria; Carmeliet, Peter.
Afiliación
  • Quaegebeur A; Laboratory of Angiogenesis and Neurovascular link, Department of Oncology, University of Leuven, Leuven, Belgium; Laboratory of Angiogenesis and Neurovascular link, Vesalius Research Center, VIB, Leuven, Belgium.
  • Segura I; Laboratory of Angiogenesis and Neurovascular link, Department of Oncology, University of Leuven, Leuven, Belgium; Laboratory of Angiogenesis and Neurovascular link, Vesalius Research Center, VIB, Leuven, Belgium.
  • Schmieder R; Laboratory of Cellular Metabolism and Metabolic Regulation, Department of Oncology, University of Leuven, Leuven, Belgium; Laboratory of Cellular Metabolism and Metabolic Regulation, Vesalius Research Center, VIB, Leuven, Belgium.
  • Verdegem D; Laboratory of Angiogenesis and Neurovascular link, Department of Oncology, University of Leuven, Leuven, Belgium; Laboratory of Angiogenesis and Neurovascular link, Vesalius Research Center, VIB, Leuven, Belgium; Metabolomics Expertise Center, Vesalius Research Center, VIB, Leuven, Belgium.
  • Decimo I; Laboratory of Angiogenesis and Neurovascular link, Department of Oncology, University of Leuven, Leuven, Belgium; Laboratory of Angiogenesis and Neurovascular link, Vesalius Research Center, VIB, Leuven, Belgium.
  • Bifari F; Laboratory of Angiogenesis and Neurovascular link, Department of Oncology, University of Leuven, Leuven, Belgium; Laboratory of Angiogenesis and Neurovascular link, Vesalius Research Center, VIB, Leuven, Belgium.
  • Dresselaers T; Biomedical MRI/Mosaic, Department of Imaging and Pathology, University of Leuven, Leuven, Belgium.
  • Eelen G; Laboratory of Angiogenesis and Neurovascular link, Department of Oncology, University of Leuven, Leuven, Belgium; Laboratory of Angiogenesis and Neurovascular link, Vesalius Research Center, VIB, Leuven, Belgium.
  • Ghosh D; Laboratory of Ion Channel Research and TRP channel research platform Leuven, Department of Cellular and Molecular Medicine, University of Leuven, Leuven, Belgium.
  • Davidson SM; Koch Institute for Integrative Cancer Research at Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
  • Schoors S; Laboratory of Angiogenesis and Neurovascular link, Department of Oncology, University of Leuven, Leuven, Belgium; Laboratory of Angiogenesis and Neurovascular link, Vesalius Research Center, VIB, Leuven, Belgium.
  • Broekaert D; Laboratory of Cellular Metabolism and Metabolic Regulation, Department of Oncology, University of Leuven, Leuven, Belgium; Laboratory of Cellular Metabolism and Metabolic Regulation, Vesalius Research Center, VIB, Leuven, Belgium.
  • Cruys B; Laboratory of Angiogenesis and Neurovascular link, Department of Oncology, University of Leuven, Leuven, Belgium; Laboratory of Angiogenesis and Neurovascular link, Vesalius Research Center, VIB, Leuven, Belgium.
  • Govaerts K; Biomedical MRI/Mosaic, Department of Imaging and Pathology, University of Leuven, Leuven, Belgium.
  • De Legher C; Laboratory of Angiogenesis and Neurovascular link, Department of Oncology, University of Leuven, Leuven, Belgium; Laboratory of Angiogenesis and Neurovascular link, Vesalius Research Center, VIB, Leuven, Belgium.
  • Bouché A; Laboratory of Angiogenesis and Neurovascular link, Department of Oncology, University of Leuven, Leuven, Belgium; Laboratory of Angiogenesis and Neurovascular link, Vesalius Research Center, VIB, Leuven, Belgium.
  • Schoonjans L; Laboratory of Angiogenesis and Neurovascular link, Department of Oncology, University of Leuven, Leuven, Belgium; Laboratory of Angiogenesis and Neurovascular link, Vesalius Research Center, VIB, Leuven, Belgium.
  • Ramer MS; Laboratory of Angiogenesis and Neurovascular link, Department of Oncology, University of Leuven, Leuven, Belgium; Laboratory of Angiogenesis and Neurovascular link, Vesalius Research Center, VIB, Leuven, Belgium; International Collaboration on Repair Discoveries, the University of British Columbia,
  • Hung G; Isis Pharmaceuticals, Carlsbad, CA 92008, USA.
  • Bossaert G; Leuven Statistics Research Centre (LStat), University of Leuven, Leuven, Belgium.
  • Cleveland DW; Ludwig Institute for Cancer Research, Department of Medicine and Neuroscience, University of California, San Diego, La Jolla, CA 92093, USA.
  • Himmelreich U; Biomedical MRI/Mosaic, Department of Imaging and Pathology, University of Leuven, Leuven, Belgium.
  • Voets T; Laboratory of Ion Channel Research and TRP channel research platform Leuven, Department of Cellular and Molecular Medicine, University of Leuven, Leuven, Belgium.
  • Lemmens R; Laboratory of Neurobiology, Vesalius Research Center, VIB, Leuven, Belgium; Experimental Neurology (Department of Neurosciences) and Leuven Research Institute for Neuroscience and Disease (LIND), University of Leuven, Leuven, Belgium; Neurology, University Hospitals Leuven, Leuven, Belgium.
  • Bennett CF; Isis Pharmaceuticals, Carlsbad, CA 92008, USA.
  • Robberecht W; Laboratory of Neurobiology, Vesalius Research Center, VIB, Leuven, Belgium; Experimental Neurology (Department of Neurosciences) and Leuven Research Institute for Neuroscience and Disease (LIND), University of Leuven, Leuven, Belgium; Neurology, University Hospitals Leuven, Leuven, Belgium.
  • De Bock K; Laboratory of Angiogenesis and Neurovascular link, Department of Oncology, University of Leuven, Leuven, Belgium; Laboratory of Angiogenesis and Neurovascular link, Vesalius Research Center, VIB, Leuven, Belgium.
  • Dewerchin M; Laboratory of Angiogenesis and Neurovascular link, Department of Oncology, University of Leuven, Leuven, Belgium; Laboratory of Angiogenesis and Neurovascular link, Vesalius Research Center, VIB, Leuven, Belgium.
  • Ghesquière B; Metabolomics Expertise Center, Vesalius Research Center, VIB, Leuven, Belgium.
  • Fendt SM; Laboratory of Cellular Metabolism and Metabolic Regulation, Department of Oncology, University of Leuven, Leuven, Belgium; Laboratory of Cellular Metabolism and Metabolic Regulation, Vesalius Research Center, VIB, Leuven, Belgium.
  • Carmeliet P; Laboratory of Angiogenesis and Neurovascular link, Department of Oncology, University of Leuven, Leuven, Belgium; Laboratory of Angiogenesis and Neurovascular link, Vesalius Research Center, VIB, Leuven, Belgium. Electronic address: peter.carmeliet@vib-kuleuven.be.
Cell Metab ; 23(2): 280-91, 2016 Feb 09.
Article en En | MEDLINE | ID: mdl-26774962
The oxygen-sensing prolyl hydroxylase domain proteins (PHDs) regulate cellular metabolism, but their role in neuronal metabolism during stroke is unknown. Here we report that PHD1 deficiency provides neuroprotection in a murine model of permanent brain ischemia. This was not due to an increased collateral vessel network. Instead, PHD1(-/-) neurons were protected against oxygen-nutrient deprivation by reprogramming glucose metabolism. Indeed, PHD1(-/-) neurons enhanced glucose flux through the oxidative pentose phosphate pathway by diverting glucose away from glycolysis. As a result, PHD1(-/-) neurons increased their redox buffering capacity to scavenge oxygen radicals in ischemia. Intracerebroventricular injection of PHD1-antisense oligonucleotides reduced the cerebral infarct size and neurological deficits following stroke. These data identify PHD1 as a regulator of neuronal metabolism and a potential therapeutic target in ischemic stroke.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Oxígeno / Isquemia Encefálica / Eliminación de Gen / Procolágeno-Prolina Dioxigenasa / Accidente Cerebrovascular / Reprogramación Celular / Neuronas Tipo de estudio: Prognostic_studies Límite: Animals Idioma: En Revista: Cell Metab Asunto de la revista: METABOLISMO Año: 2016 Tipo del documento: Article País de afiliación: Bélgica Pais de publicación: Estados Unidos
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Oxígeno / Isquemia Encefálica / Eliminación de Gen / Procolágeno-Prolina Dioxigenasa / Accidente Cerebrovascular / Reprogramación Celular / Neuronas Tipo de estudio: Prognostic_studies Límite: Animals Idioma: En Revista: Cell Metab Asunto de la revista: METABOLISMO Año: 2016 Tipo del documento: Article País de afiliación: Bélgica Pais de publicación: Estados Unidos