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

Benjamin A. Olenchock | Zendy; Javid J. Moslehi | Zendy; Alan H. Baik | Zendy; Shawn M. Davidson | Zendy; Jeremy Williams | Zendy; William J. Gibson | Zendy; Abhishek A. Chakraborty | Zendy; Kerry A. Pierce | Zendy; Christine Miller | Zendy; Eric A. Hanse | Zendy; Ameeta Kelekar | Zendy; Lucas B. Sullivan | Zendy; Amy J. Wagers | Zendy; Clary B. Clish | Zendy; Matthew G. Vander Heiden | Zendy; William G. Kaelin | Zendy

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

Author(s) -

Benjamin A. Olenchock,

Javid J. Moslehi,

Alan H. Baik,

Shawn M. Davidson,

Jeremy Williams,

William J. Gibson,

Abhishek A. Chakraborty,

Kerry A. Pierce,

Christine Miller,

Eric A. Hanse,

Ameeta Kelekar,

Lucas B. Sullivan,

Amy J. Wagers,

Clary B. Clish,

Matthew G. Vander Heiden,

William G. Kaelin

Publication year - 2016

Publication title -

cell

Language(s) - English

Resource type - Journals

SCImago Journal Rank - 26.304

H-Index - 776

eISSN - 1097-4172

pISSN - 0092-8674

DOI - 10.1016/j.cell.2016.03.037

Subject(s) - biology , kynurenic acid , metabolite , biochemistry , substrate (aquarium) , skeletal muscle , pharmacology , anatomy , ecology , tryptophan , amino acid

Summary 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 (αKG)-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 αKG, which drives hepatic production and secretion of kynurenic acid (KYNA) that is necessary and sufficient to mediate cardiac ischemic protection in this setting.

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