Deletion or Inhibition of the Oxygen Sensor PHD1 Protects against Ischemic Stroke via Reprogramming of Neuronal Metabolism
| Autor: | Don W. Cleveland, Tom Dresselaers, Bert Cruys, Matt S. Ramer, Annelies Quaegebeur, Gene Hung, Goele Bossaert, Carla De Legher, Sarah-Maria Fendt, Ann Bouché, Bart Ghesquière, Roberta Schmieder, Peter Carmeliet, Inmaculada Segura, Francesco Bifari, Guy Eelen, Ilaria Decimo, Mieke Dewerchin, Wim Robberecht, Kristof Govaerts, Shawn M. Davidson, Robin Lemmens, Dorien Broekaert, Sandra Schoors, Debapriya Ghosh, Luc Schoonjans, Dries Verdegem, C. Frank Bennett, Katrien De Bock, Uwe Himmelreich, Thomas Voets |
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| Jazyk: | angličtina |
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Physiology Oligonucleotides Medical Biochemistry and Metabolomics Brain Ischemia Brain ischemia Pentose Phosphate Pathway Mice 2.1 Biological and endogenous factors Glycolysis Aetiology Stroke Mice Knockout Neurons Brain Free Radical Scavengers Cellular Reprogramming Neuroprotection Cell biology Phenotype Biochemistry Neurological Procollagen-proline dioxygenase Hypoxia-Inducible Factor 1 Oxidation-Reduction Knockout Intraventricular 1.1 Normal biological development and functioning Ischemia Procollagen-Proline Dioxygenase Carbohydrate metabolism Biology Pentose phosphate pathway alpha Subunit Hydroxylation Article Injections 03 medical and health sciences Endocrinology & Metabolism Underpinning research medicine Animals Carbon Hypoxia-Inducible Factor 1 alpha Subunit Injections Intraventricular Oxygen Reactive Oxygen Species Gene Deletion Molecular Biology Nutrition Neurosciences Cell Biology medicine.disease Brain Disorders 030104 developmental biology Biochemistry and Cell Biology |
| Zdroj: | Cell metabolism, vol 23, iss 2 |
| Popis: | 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. publisher: Elsevier articletitle: Deletion or Inhibition of the Oxygen Sensor PHD1 Protects against Ischemic Stroke via Reprogramming of Neuronal Metabolism journaltitle: Cell Metabolism articlelink: http://dx.doi.org/10.1016/j.cmet.2015.12.007 content_type: article copyright: Copyright © 2016 Elsevier Inc. All rights reserved. ispartof: Cell Metabolism vol:23 issue:2 pages:280-291 ispartof: location:United States status: published |
| Databáze: | OpenAIRE |
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