EGLN1 Inhibition and Rerouting of α-Ketoglutarate Suffice for Remote Ischemic Protection

被引：126

作者：

Olenchock, Benjamin A. ^{[1
,2
,3
]}

Moslehi, Javid ^{[4
]}

Baik, Alan H. ^{[5
]}

Davidson, Shawn M. ^{[3
]}

Williams, Jeremy ^{[6
]}

Gibson, William J. ^{[2
,6
]}

Pierce, Kerry A. ^{[7
]}

Miller, Christine M. ^{[8
,9
]}

Hanse, Eric A. ^{[10
,11
]}

Kelekar, Ameeta ^{[10
,11
]}

Sullivan, Lucas B. ^{[3
]}

Wagers, Amy J. ^{[8
,9
]}

Clish, Clary B. ^{[7
]}

Vander Heiden, Matthew G. ^{[3
,6
]}

Kaelin, William G., Jr. ^{[2
,6
,12
]}

机构：

[1] Brigham & Womens Hosp, Dept Med, Div Cardiovasc Med, 75 Francis St, Boston, MA 02115 USA

[2] Harvard Univ, Sch Med, Boston, MA 02115 USA

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

[4] Vanderbilt Univ Sch Med, Dept Med, Div Cardiovasc Med, Nashville, TN 37235 USA

[5] Univ San Francisco, Dept Med, San Francisco, CA 94117 USA

[6] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA

[7] Broad Inst, Metabol Platform, Cambridge, MA 02142 USA

[8] Harvard Univ, Dept Stem Cell & Regenerat Biol, Cambridge, MA 02138 USA

[9] Joslin Diabet Ctr, Boston, MA 02215 USA

[10] Univ Minnesota, Dept Lab Med & Pathol, Minneapolis, MN 55455 USA

[11] Univ Minnesota, Masonic Canc Ctr, Minneapolis, MN 55455 USA

[12] Howard Hughes Med Inst, Chevy Chase, MD 20815 USA

来源：

CELL | 2016年 / 164卷 / 05期

关键词：

REDUCTIVE GLUTAMINE-METABOLISM; PROLYL HYDROXYLASE-ACTIVITY; MYOCARDIAL-INFARCTION; HYPOXIA; HEART; 4-HYDROXYLASE; ALTERS; ERYTHROPOIETIN; EXPRESSION; PROFILES;

D O I：

10.1016/j.cell.2016.02.006

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

070307 [化学生物学]; 071010 [生物化学与分子生物学];

摘要：

Ischemic preconditioning is the phenomenon whereby brief periods of sublethal ischemia protect against a subsequent, more prolonged, ischemic insult. In remote ischemic preconditioning (RIPC), ischemia to one organ protects others organs at a distance. We created mouse models to ask if inhibition of the alpha-ketoglutarate (alpha KG)-dependent dioxygenase Egln1, which senses oxygen and regulates the hypoxia-inducible factor (HIF) transcription factor, could suffice to mediate local and remote ischemic preconditioning. Using somatic gene deletion and a pharmacological inhibitor, we found that inhibiting Egln1 systemically or in skeletal muscles protects mice against myocardial ischemia-reperfusion (I/R) injury. Parabiosis experiments confirmed that RIPC in this latter model was mediated by a secreted factor. Egln1 loss causes accumulation of circulating alpha KG, which drives hepatic production and secretion of kynurenic acid (KYNA) that is necessary and sufficient to mediate cardiac ischemic protection in this setting.

引用

页码：884 / 895

页数：12

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