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

doi:10.1016/j.cmet.2015.12.007

Deletion or Inhibition of the Oxygen Sensor PHD1 Protects against Ischemic Stroke via Reprogramming of Neuronal Metabolism

Author:

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

Keywords:

Science & Technology, Life Sciences & Biomedicine, Cell Biology, Endocrinology & Metabolism, BRAIN, HYPOXIA, TIGAR, GLUCOSE-6-PHOSPHATE-DEHYDROGENASE, GLUTATHIONE, GLYCOLYSIS, DEFICIENCY, TOLERANCE, CROSSROAD, PATHWAY, Animals, Brain, Brain Ischemia, Carbon, Cellular Reprogramming, Free Radical Scavengers, Gene Deletion, Hydroxylation, Hypoxia-Inducible Factor 1, alpha Subunit, Injections, Intraventricular, Mice, Knockout, Neurons, Neuroprotection, Oligonucleotides, Oxidation-Reduction, Oxygen, Pentose Phosphate Pathway, Phenotype, Procollagen-Proline Dioxygenase, Reactive Oxygen Species, Stroke, 0601 Biochemistry and Cell Biology, 1101 Medical Biochemistry and Metabolomics, 3101 Biochemistry and cell biology, 3205 Medical biochemistry and metabolomics

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.