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

被引：73

作者：

Quaegebeur, Annelies ^{[1
,2
]}

Segura, Inmaculada ^{[1
,2
]}

Schmieder, Roberta ^{[3
,4
]}

Verdegem, Dries ^{[1
,2
,5
]}

Decimo, Ilaria ^{[1
,2
]}

Bifari, Francesco ^{[1
,2
]}

Dresselaers, Tom ^{[6
]}

Eelen, Guy ^{[1
,2
]}

Ghosh, Debapriva ^{[7
]}

Davidson, Shawn M. ^{[8
]}

Schoors, Sandra ^{[1
,2
]}

Broekaert, Dorien ^{[3
,4
]}

Cruys, Bert ^{[1
,2
]}

Govaerts, Kristof ^{[6
]}

De Legher, Carla ^{[1
,2
]}

Bouche, Ann ^{[1
,2
]}

Schoonjans, Luc ^{[1
,2
]}

Ramer, Matt S. ^{[1
,2
,9
]}

Hung, Gene ^{[10
]}

Bossaert, Goele ^{[11
]}

Cleveland, Don W. ^{[2
,12
]}

Himmelreich, Uwe ^{[6
]}

Voets, Thomas ^{[7
]}

Lemmens, Robin ^{[13
,14
,15
,16
]}

Bennett, C. Frank ^{[10
]}

Robberecht, Wim ^{[13
,14
,15
,16
]}

De Bock, Katrien ^{[1
,2
,17
]}

Dewerchin, Mieke ^{[1
,2
]}

Ghesquiere, Bart ^{[5
]}

Fendt, Sarah-Maria ^{[3
,4
]}

Carmeliet, Peter ^{[1
,2
]}

机构：

[1] Univ Leuven, Dept Oncol, Lab Angiogenesis & Neurovasc Link, Leuven, Belgium

[2] VIB, Vesalius Res Ctr, Lab Angiogenesis & Neurovasc Link, Leuven, Belgium

[3] Univ Leuven, Dept Oncol, Lab Cellular Metab & Metab Regulat, Leuven, Belgium

[4] VIB, Vesalius Res Ctr, Lab Cellular Metab & Metab Regulat, Leuven, Belgium

[5] VIB, Vesalius Res Ctr, Metabol Expertise Ctr, Leuven, Belgium

[6] Univ Leuven, Dept Imaging & Pathol, Biomed MRI Mosaic, Leuven, Belgium

[7] Univ Leuven, Lab Ion Channel Res & TRP Channel Res Platform Le, Dept Cellular & Mol Med, Leuven, Belgium

[8] MIT, Koch Inst Integrat Canc Res, 77 Massachusetts Ave, Cambridge, MA 02139 USA

[9] Univ British Columbia, Int Collaborat Repair Discoveries, Vancouver, BC V5Z 1M9, Canada

[10] Isis Pharmaceut, Carlsbad, CA 92008 USA

[11] Univ Leuven, Leuven Stat Res Ctr LStat, Leuven, Belgium

[12] Univ Calif San Diego, Ludwig Inst Canc Res, Dept Med & Neurosci, La Jolla, CA 92093 USA

[13] VIB, Vesalius Res Ctr, Lab Neurobiol, Leuven, Belgium

[14] Univ Leuven, Expt Neurol, Dept Neurosci, Leuven, Belgium

[15] Univ Leuven, Leuven Res Inst Neurosci & Dis LIND, Leuven, Belgium

[16] Univ Hosp Leuven, Neurol, Leuven, Belgium

[17] ETH, Dept Hlth Sci & Technol, Lab Exercise & Hlth, Swiss Fed Inst Technol, Zurich, Switzerland

来源：

CELL METABOLISM | 2016年 / 23卷 / 02期

基金：

欧洲研究理事会;

关键词：

BRAIN; HYPOXIA; TIGAR; GLUCOSE-6-PHOSPHATE-DEHYDROGENASE; GLUTATHIONE; GLYCOLYSIS; DEFICIENCY; TOLERANCE; CROSSROAD; PATHWAY;

D O I：

10.1016/j.cmet.2015.12.007

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

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.

引用

页码：280 / 291

页数：12

共 34 条

[1] Deficiency or inhibition of oxygen sensor Phd1 induces hypoxia tolerance by reprogramming basal metabolism
Julián Aragonés
Martin Schneider
Katie Van Geyte
Peter Fraisl
Tom Dresselaers
Massimiliano Mazzone
Ruud Dirkx
Serena Zacchigna
Hélène Lemieux
Nam Ho Jeoung
Diether Lambrechts
Tammie Bishop
Peggy Lafuste
Antonio Diez-Juan
Sarah K Harten
Pieter Van Noten
Katrien De Bock
Carsten Willam
Marc Tjwa
Alexandra Grosfeld
Rachel Navet
Lieve Moons
Thierry Vandendriessche
Christophe Deroose
Bhathiya Wijeyekoon
Johan Nuyts
Benedicte Jordan
Robert Silasi-Mansat
Florea Lupu
Mieke Dewerchin
Chris Pugh
Phil Salmon
Luc Mortelmans
Bernard Gallez
Frans Gorus
Johan Buyse
Francis Sluse
Robert A Harris
Erich Gnaiger
Peter Hespel
Paul Van Hecke
Frans Schuit
Paul Van Veldhoven
Peter Ratcliffe
Myriam Baes
Patrick Maxwell
Peter Carmeliet
[J]. Nature Genetics, 2008, 40 : 170 - 180
[2] Deficiency or inhibition of oxygen sensor Phd1 induces hypoxia tolerance by reprogramming basal metabolism
Aragones, Julian
Schneider, Martin
Van Geyte, Katie
Fraisl, Peter
Dresselaers, Tom
Mazzone, Massimiliano
Dirkx, Ruud
Zacchigna, Serena
Lemieux, Helene
Jeoung, Nam Ho
Lambrechts, Diether
Bishop, Tammie
Lafuste, Peggy
Diez-Juan, Antonio
Harten, Sarah K.
Van Noten, Pieter
De Bock, Katrien
Willam, Carsten
Tjwa, Marc
Grosfeld, Alexandra
Navet, Rachel
Moons, Lieve
Vandendriessche, Thierry
Deroose, Christophe
Wijeyekoon, Bhathiya
Nuyts, Johan
Jordan, Benedicte
Silasi-Mansat, Robert
Lupu, Florea
Dewerchin, Mieke
Pugh, Chris
Salmon, Phil
Mortelmans, Luc
Gallez, Bernard
Gorus, Frans
Buyse, Johan
Sluse, Francis
Harris, Robert A.
Gnaiger, Erich
Hespel, Peter
Van Hecke, Paul
Schuit, Frans
Van Veldhoven, Paul
Ratcliffe, Peter
Baes, Myriam
Maxwell, Patrick
Carmeliet, Peter
[J]. NATURE GENETICS, 2008, 40 (02) : 170 - 180
[3] Knockdown of RGMA improves ischemic stroke via Reprogramming of Neuronal Metabolism
Wang, Zijie
Zhang, Shaoru
Cheng, Ruiqi
Jiang, Anan
Qin, Xinyue
[J]. FREE RADICAL BIOLOGY AND MEDICINE, 2024, 218 : 41 - 56
[4] Inhibition of miR-19a protects neurons against ischemic stroke through modulating glucose metabolism and neuronal apoptosis
Xiao-Li Ge
Jin-Li Wang
Xin Liu
Jia Zhang
Chang Liu
Li Guo
[J]. Cellular & Molecular Biology Letters, 2019, 24
[5] Inhibition of miR-19a protects neurons against ischemic stroke through modulating glucose metabolism and neuronal apoptosis
Ge, Xiao-Li
Wang, Jin-Li
Liu, Xin
Zhang, Jia
Liu, Chang
Guo, Li
[J]. CELLULAR & MOLECULAR BIOLOGY LETTERS, 2019, 24 (1)
[6] Preservation of GABAA Receptor Function by PTEN Inhibition Protects Against Neuronal Death in Ischemic Stroke
Liu, Baosong
Li, Lijun
Zhang, Quanguang
Chang, Ning
Wang, Dianshi
Shan, Yuexin
Li, Lei
Wang, Hanbin
Feng, Hua
Zhang, Liang
Brann, Darrell W.
Wan, Qi
[J]. STROKE, 2010, 41 (05) : 1018 - 1026
[7] Activation of the hypoxia-inducible factor pathway protects against acute ischemic stroke by reprogramming central carbon metabolism
Madai, Sarah
Kilic, Pinar
Schmidt, Rolf M.
Bas-Orth, Carlos
Korff, Thomas
Buettner, Michael
Klinke, Glynis
Poschet, Gernot
Marti, Hugo H.
Kunze, Reiner
[J]. THERANOSTICS, 2024, 14 (07): : 2856 - 2880
[8] Chloral Hydrate Preconditioning Protects Against Ischemic Stroke via Upregulating Annexin A1
Liu, Jiu-Hong
Feng, Dan
Zhang, Yu-Fen
Shang, You
Wu, Yan
Li, Xiao-Feng
Pei, Lei
[J]. CNS NEUROSCIENCE & THERAPEUTICS, 2015, 21 (09) : 718 - 726
[9] Ginkgolide B Protects Against Ischemic Stroke via Targeting AMPK/PINK1
Cao, Yile
Yang, Lei
Cheng, Hong
[J]. FRONTIERS IN PHARMACOLOGY, 2022, 13
[10] Atorvastatin protects against cerebral infarction via inhibition of NADPH oxidase-derived superoxide in ischemic stroke
Hong, Hua
Zeng, Jin-Sheng
Kreulen, David L.
Kaufman, David I.
Chen, Alex F.
[J]. AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY, 2006, 291 (05): : H2210 - H2215

← 1 2 3 4 →