| Literature DB >> 26774962 |
Annelies Quaegebeur1, Inmaculada Segura1, Roberta Schmieder2, Dries Verdegem3, Ilaria Decimo1, Francesco Bifari1, Tom Dresselaers4, Guy Eelen1, Debapriva Ghosh5, Shawn M Davidson6, Sandra Schoors1, Dorien Broekaert2, Bert Cruys1, Kristof Govaerts4, Carla De Legher1, Ann Bouché1, Luc Schoonjans1, Matt S Ramer7, Gene Hung8, Goele Bossaert9, Don W Cleveland10, Uwe Himmelreich4, Thomas Voets5, Robin Lemmens11, C Frank Bennett8, Wim Robberecht11, Katrien De Bock1, Mieke Dewerchin1, Bart Ghesquière12, Sarah-Maria Fendt2, Peter Carmeliet13.
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.Entities:
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Year: 2016 PMID： 26774962 PMCID： PMC4880550 DOI： 10.1016/j.cmet.2015.12.007
Source DB: PubMed Journal: Cell Metab ISSN： 1550-4131 Impact factor: 27.287