title: Deletion or Inhibition of the Oxygen Sensor PHD1 Protects against Ischemic Stroke via Reprogramming of Neuronal Metabolism.
abstract: 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.
authors.affiliation: 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.
authors.forename: Annelies
authors.initials: A
authors.lastname: Quaegebeur
authors.affiliation: 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.
authors.forename: Inmaculada
authors.initials: I
authors.lastname: Segura
authors.affiliation: 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.
authors.forename: Roberta
authors.initials: R
authors.lastname: Schmieder
authors.affiliation: 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.
authors.forename: Dries
authors.initials: D
authors.lastname: Verdegem
authors.affiliation: 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.
authors.forename: Ilaria
authors.initials: I
authors.lastname: Decimo
authors.affiliation: 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.
authors.forename: Francesco
authors.initials: F
authors.lastname: Bifari
authors.affiliation: Biomedical MRI/Mosaic, Department of Imaging and Pathology, University of Leuven, Leuven, Belgium.
authors.forename: Tom
authors.initials: T
authors.lastname: Dresselaers
authors.affiliation: 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.
authors.forename: Guy
authors.initials: G
authors.lastname: Eelen
authors.affiliation: Laboratory of Ion Channel Research and TRP channel research platform Leuven, Department of Cellular and Molecular Medicine, University of Leuven, Leuven, Belgium.
authors.forename: Debapriva
authors.initials: D
authors.lastname: Ghosh
authors.affiliation: Koch Institute for Integrative Cancer Research at Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
authors.forename: Shawn M
authors.initials: SM
authors.lastname: Davidson
authors.affiliation: 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.
authors.forename: Sandra
authors.initials: S
authors.lastname: Schoors
authors.affiliation: 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.
authors.forename: Dorien
authors.initials: D
authors.lastname: Broekaert
authors.affiliation: 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.
authors.forename: Bert
authors.initials: B
authors.lastname: Cruys
authors.affiliation: Biomedical MRI/Mosaic, Department of Imaging and Pathology, University of Leuven, Leuven, Belgium.
authors.forename: Kristof
authors.initials: K
authors.lastname: Govaerts
authors.affiliation: 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.
authors.forename: Carla
authors.initials: C
authors.lastname: De Legher
authors.affiliation: 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.
authors.forename: Ann
authors.initials: A
authors.lastname: Bouché
authors.affiliation: 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.
authors.forename: Luc
authors.initials: L
authors.lastname: Schoonjans
authors.affiliation: 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, Vancouver, Canada.
authors.forename: Matt S
authors.initials: MS
authors.lastname: Ramer
authors.affiliation: Isis Pharmaceuticals, Carlsbad, CA 92008, USA.
authors.forename: Gene
authors.initials: G
authors.lastname: Hung
authors.affiliation: Leuven Statistics Research Centre (LStat), University of Leuven, Leuven, Belgium.
authors.forename: Goele
authors.initials: G
authors.lastname: Bossaert
authors.affiliation: Ludwig Institute for Cancer Research, Department of Medicine and Neuroscience, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Don W
authors.initials: DW
authors.lastname: Cleveland
authors.affiliation: Biomedical MRI/Mosaic, Department of Imaging and Pathology, University of Leuven, Leuven, Belgium.
authors.forename: Uwe
authors.initials: U
authors.lastname: Himmelreich
authors.affiliation: Laboratory of Ion Channel Research and TRP channel research platform Leuven, Department of Cellular and Molecular Medicine, University of Leuven, Leuven, Belgium.
authors.forename: Thomas
authors.initials: T
authors.lastname: Voets
authors.affiliation: 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.
authors.forename: Robin
authors.initials: R
authors.lastname: Lemmens
authors.affiliation: Isis Pharmaceuticals, Carlsbad, CA 92008, USA.
authors.forename: C Frank
authors.initials: CF
authors.lastname: Bennett
authors.affiliation: 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.
authors.forename: Wim
authors.initials: W
authors.lastname: Robberecht
authors.affiliation: 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.
authors.forename: Katrien
authors.initials: K
authors.lastname: De Bock
authors.affiliation: 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.
authors.forename: Mieke
authors.initials: M
authors.lastname: Dewerchin
authors.affiliation: Metabolomics Expertise Center, Vesalius Research Center, VIB, Leuven, Belgium.
authors.forename: Bart
authors.initials: B
authors.lastname: Ghesquière
authors.affiliation: 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.
authors.forename: Sarah-Maria
authors.initials: SM
authors.lastname: Fendt
authors.affiliation: 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.
authors.forename: Peter
authors.initials: P
authors.lastname: Carmeliet
mesh_terms: D000818:Animals; D001921:Brain / Q000098:blood supply / Q000187:drug effects / Q000473:pathology; D002545:Brain Ischemia / Q000150:complications / Q000517:prevention & control*; D002244:Carbon / Q000378:metabolism; D065150:Cellular Reprogramming / Q000187:drug effects; D016166:Free Radical Scavengers / Q000378:metabolism; D017353:Gene Deletion; D006900:Hydroxylation; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D007276:Injections, Intraventricular; D018345:Mice, Knockout; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D000066829:Neuroprotection / Q000187:drug effects; D009841:Oligonucleotides / Q000008:administration & dosage / Q000494:pharmacology; D010084:Oxidation-Reduction / Q000187:drug effects; D010100:Oxygen / Q000378:metabolism*; D010427:Pentose Phosphate Pathway / Q000187:drug effects; D010641:Phenotype; D011393:Procollagen-Proline Dioxygenase / Q000172:deficiency / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D020521:Stroke / Q000150:complications / Q000517:prevention & control*
chemical_list: D016166:Free Radical Scavengers; C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009841:Oligonucleotides; D017382:Reactive Oxygen Species; D002244:Carbon; C522721:PHD1 protein, mouse; D011393:Procollagen-Proline Dioxygenase; D010100:Oxygen