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

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

Research output: Contribution to journalArticlepeer-review

95 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)884-895
Number of pages12
JournalCell
Volume164
Issue number5
DOIs
StatePublished - Feb 25 2016

Bibliographical note

Publisher Copyright:
© 2016 Elsevier Inc.

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