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

Cell Metabolism
Annelies QuaegebeurPeter Carmeliet

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.

References

Jul 6, 2000·Progress in Neurobiology·R Dringen
Jan 10, 2001·Journal of Cerebral Blood Flow and Metabolism : Official Journal of the International Society of Cerebral Blood Flow and Metabolism·P H Chan
Jun 1, 2002·Bioorganic & Medicinal Chemistry Letters·Luke A McNeillChristopher J Schofield
Jul 13, 2004·The Journal of Biological Chemistry·Rebecca J AppelhoffJonathan M Gleadle
Jul 15, 2006·Cell·Karim BensaadKaren H Vousden
Feb 22, 2008·Molecular Biology of the Cell·Mauricio G MartinCarlos G Dotti
Dec 25, 2008·Annals of Neurology·Sang Won SuhRaymond A Swanson
Jan 2, 2009·Cell Metabolism·Julián AragonésPeter Carmeliet
Jan 24, 2009·Nature Reviews. Drug Discovery·Peter FraislPeter Carmeliet
Oct 3, 2009·Nature Protocols·Valentine BouetThomas Freret
Jul 31, 2010·Neuron·Michael A MoskowitzCostantino Iadecola
Dec 8, 2010·Journal of Neuroscience Methods·Bruno P MeloniNeville W Knuckey
Mar 17, 2012·Cell Death and Differentiation·P Rodriguez-RodriguezJ P Bolaños
Mar 21, 2012·IUBMB Life·Robert C Stanton
Dec 4, 2012·Trends in Biochemical Sciences·Brian W WongPeter Carmeliet
Dec 12, 2012·Cell Metabolism·Aparna Oruganty-DasJoel D Richter
Jan 31, 2013·Biological Chemistry·Carsten C Scholz, Cormac T Taylor
Mar 16, 2013·Acta Physiologica·J Myllyharju
Aug 24, 2013·Trends in Neurosciences·Philipp MergenthalerAndreas Meisel
Mar 29, 2014·The Journal of Experimental Biology·John LarsonThomas J Park
May 30, 2014·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Mei LiZheng-Hong Qin
Apr 2, 2015·Nature·Sandra SchoorsPeter Carmeliet

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Citations

Jul 2, 2016·Nature Reviews. Neurology·Christian LangePeter Carmeliet
Mar 20, 2016·Journal of Cerebral Blood Flow and Metabolism : Official Journal of the International Society of Cerebral Blood Flow and Metabolism·Tom StruysTom Dresselaers
May 10, 2017·Proceedings of the National Academy of Sciences of the United States of America·Michele FerrariWarren M Zapol
Feb 1, 2018·International Journal of Molecular Sciences·Joshua M KaplanSean Dikdan
Jul 5, 2018·Journal of Cerebral Blood Flow and Metabolism : Official Journal of the International Society of Cerebral Blood Flow and Metabolism·Alberto CataneseTobias M Boeckers
Feb 13, 2018·The Journal of Physiology·Kilian B KennelCormac T Taylor
Apr 28, 2018·Circulation Research·Steven J ForresterKathy K Griendling
Aug 31, 2017·Nature Reviews. Gastroenterology & Hepatology·Sophie Van WeldenPieter Hindryckx
Sep 21, 2019·Physiological Reviews·Eoin P CumminsCormac T Taylor
May 6, 2020·Neurotherapeutics : the Journal of the American Society for Experimental NeuroTherapeutics·Melika HosseiniYama Akbari
Dec 22, 2016·Oncotarget·Hugo H Marti, Reiner Kunze
Jul 28, 2016·Oncotarget·Pablo J Fernandez-Marcos, Sandrina Nóbrega-Pereira
Oct 6, 2019·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Hu HuangLijuan Fan
Jan 7, 2020·Aging·Jiayan WuXueyuan Liu
Nov 1, 2017·Frontiers in Molecular Neuroscience·Juliane SünwoldtPhilipp Mergenthaler
Mar 20, 2018·Acta Neuropathologica·Tijs VandoorneLudo Van Den Bosch
Nov 3, 2016·The Journal of Biological Chemistry·Ying-Hui KoUbaldo Martinez-Outschoorn
Jun 30, 2019·Frontiers in Molecular Neuroscience·Giuseppe MartanoFrancesco Bifari
Oct 27, 2018·Frontiers in Cell and Developmental Biology·Ruoli ChenNicholas R Forsyth
Jan 30, 2021·Acta Pharmacologica Sinica·Jie TangRui Sheng
Feb 16, 2021·Frontiers in Molecular Neuroscience·Christian Lange, Francesco Bifari
Jun 4, 2021·Neurochemistry International·Qi-Qi LiRui Sheng
Jun 29, 2021·Pharmacological Research : the Official Journal of the Italian Pharmacological Society·Zirong PanGuanhua Du
Jun 13, 2021·Progress in Neurobiology·Shuai ZhangXiaofeng Jia
Dec 8, 2021·Development·Yida JiangGuo-Hua Fong

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