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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
- et al.
Published Web Location
https://doi.org/10.1016/j.cmet.2015.12.007Abstract
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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