Deficiency or inhibition of oxygen sensor Phd1 induces hypoxia tolerance by reprogramming basal metabolism

被引：397

作者：

Aragones, Julian ^{[1
,2
]}

Schneider, Martin ^{[1
,2
]}

Van Geyte, Katie ^{[1
,2
]}

Fraisl, Peter ^{[1
,2
]}

Dresselaers, Tom ^{[3
]}

Mazzone, Massimiliano ^{[1
,2
]}

Dirkx, Ruud ^{[4
]}

Zacchigna, Serena ^{[1
,2
]}

Lemieux, Helene ^{[2
,5
]}

Jeoung, Nam Ho ^{[6
]}

Lambrechts, Diether ^{[1
,2
]}

Bishop, Tammie ^{[7
]}

Lafuste, Peggy ^{[1
,2
]}

Diez-Juan, Antonio ^{[1
,2
]}

Harten, Sarah K. ^{[8
]}

Van Noten, Pieter ^{[9
]}

De Bock, Katrien ^{[9
]}

Willam, Carsten ^{[7
]}

Tjwa, Marc ^{[1
,2
]}

Grosfeld, Alexandra ^{[7
]}

Navet, Rachel ^{[10
]}

Moons, Lieve ^{[1
,2
]}

Vandendriessche, Thierry ^{[1
,2
]}

Deroose, Christophe ^{[11
]}

Wijeyekoon, Bhathiya ^{[7
]}

Nuyts, Johan ^{[11
]}

Jordan, Benedicte ^{[12
]}

Silasi-Mansat, Robert ^{[13
]}

Lupu, Florea ^{[13
]}

Dewerchin, Mieke ^{[1
,2
]}

Pugh, Chris ^{[7
]}

Salmon, Phil ^{[14
]}

Mortelmans, Luc ^{[11
]}

Gallez, Bernard ^{[12
]}

Gorus, Frans ^{[15
]}

Buyse, Johan ^{[16
]}

Sluse, Francis ^{[10
]}

Harris, Robert A. ^{[6
]}

Gnaiger, Erich ^{[5
]}

Hespel, Peter ^{[9
]}

Van Hecke, Paul ^{[3
]}

Schuit, Frans ^{[17
]}

Van Veldhoven, Paul ^{[18
]}

Ratcliffe, Peter ^{[7
]}

Baes, Myriam ^{[4
]}

Maxwell, Patrick ^{[8
]}

Carmeliet, Peter ^{[1
,2
]}

机构：

[1] Katholieke Univ Leuven, Ctr Transgene Technol & Gene Therapy, B-3000 Louvain, Belgium

[2] Katholieke Univ Leuven VIB, Dept Transgene Technol & Gene Therapy, B-3000 Louvain, Belgium

[3] Katholieke Univ Leuven, Biomed MRI Unit, B-3000 Louvain, Belgium

[4] Katholieke Univ Leuven, Lab Cell Metab, B-3000 Louvain, Belgium

[5] Med Univ Innsbruck, Dept Transplant Surg, D Swarovski Res Lab, A-6020 Innsbruck, Austria

[6] Indiana Univ, Sch Med, Dept Biochem & Mol Biol, Indianapolis, IN 46202 USA

[7] Henry Wellcome Bldg Mol Physiol, Oxford OX3 7BN, England

[8] Univ London Imperial Coll Sci Technol & Med, Div Med, London W12 0NN, England

[9] Katholieke Univ Leuven, Fac Kinesiol & Rehabil Sci, Exercise & Hlth Lab, B-3001 Louvain, Belgium

[10] Univ Liege, Dept Life Sci, Lab Bioenerget & Mol Physiol, B-4000 Liege, Belgium

[11] Katholieke Univ Leuven, Univ Hosp, Dept Nucl Med, B-3000 Louvain, Belgium

[12] Catholic Univ Louvain, Biomed Magnet Resonance Unit, B-1200 Brussels, Belgium

[13] Oklahoma Med Res Fdn, Cardiovasc Res Program, Oklahoma City, OK 73104 USA

[14] Skyscan NV, B-2630 Aartselaar, Belgium

[15] Free Univ Brussels, Diabet Res Ctr, B-1090 Brussels, Belgium

[16] Katholieke Univ Leuven, Dept Biosyst, Lab Physiol Immunol & Genet Domest Anim, B-3001 Louvain, Belgium

[17] Katholieke Univ Leuven, Dept Mol Cell Biol, Gene Express Unit, B-3000 Louvain, Belgium

[18] Katholieke Univ Leuven, Lab Lipid Biochem & Prot Interact, Dept Mol Cell Biol, B-3000 Louvain, Belgium

来源：

NATURE GENETICS | 2008年 / 40卷 / 02期

基金：

英国医学研究理事会;

关键词：

D O I：

10.1038/ng.2007.62

中图分类号：

Q3 [遗传学];

学科分类号：

071007 [遗传学]; 090102 [作物遗传育种];

摘要：

HIF prolyl hydroxylases (PHD1-3) are oxygen sensors that regulate the stability of the hypoxia-inducible factors (HIFs) in an oxygen-dependent manner. Here, we show that loss of Phd1 lowers oxygen consumption in skeletal muscle by reprogramming glucose metabolism from oxidative to more anaerobic ATP production through activation of a Ppar alpha pathway. This metabolic adaptation to oxygen conservation impairs oxidative muscle performance in healthy conditions, but it provides acute protection of myofibers against lethal ischemia. Hypoxia tolerance is not due to HIF-dependent angiogenesis, erythropoiesis or vasodilation, but rather to reduced generation of oxidative stress, which allows Phd1-deficient myofibers to preserve mitochondrial respiration. Hypoxia tolerance relies primarily on Hif-2 alpha and was not observed in heterozygous Phd2-deficient or homozygous Phd3-deficient mice. Of medical importance, conditional knockdown of Phd1 also rapidly induces hypoxia tolerance. These findings delineate a new role of Phd1 in hypoxia tolerance and offer new treatment perspectives for disorders characterized by oxidative stress.

引用

页码：170 / 180

页数：11

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