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

被引：83

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

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