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

doi:10.1016/j.cell.2016.02.006

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

Laboratory Medicine and Pathology

Research output: Contribution to journal › Article › peer-review

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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 language	English (US)
Pages (from-to)	884-895
Number of pages	12
Journal	Cell
Volume	164
Issue number	5
DOIs	https://doi.org/10.1016/j.cell.2016.02.006
State	Published - Feb 25 2016

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© 2016 Elsevier Inc.

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Olenchock, B. A., Moslehi, J., Baik, A. H., Davidson, S. M., Williams, J., Gibson, W. J., Pierce, K. A., Miller, C. M., Hanse, E. A., Kelekar, A., Sullivan, L. B., Wagers, A. J., Clish, C. B., Vander Heiden, M. G., & Kaelin, W. G. (2016). EGLN1 Inhibition and Rerouting of α-Ketoglutarate Suffice for Remote Ischemic Protection. Cell, 164(5), 884-895. https://doi.org/10.1016/j.cell.2016.02.006

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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.",

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

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AU - Sullivan, Lucas B.

AU - Wagers, Amy J.

AU - Clish, Clary B.

AU - Vander Heiden, Matthew G.

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N2 - 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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EGLN1 Inhibition and Rerouting of α-Ketoglutarate Suffice for Remote Ischemic Protection

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