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^*

^*Corresponding author for this work

Medicine, Pulmonary Division

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

103 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 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

Funding

We thank Gerald Wogan, Laura Trudel, and Luiz Godoy for measuring nitrite, Rongli Lao and Souen Ngoy (Brigham and Women’s Hospital, BWH) for help with cardiac I/R injury studies, Tom Cooper (Baylor College of Medicine) for the HSA-Cre ER mice and Lee Flippin and Michael Arend (Fibrogen) for FG-4497. B.A.O. was supported by NIH K08 HL119355 and the Gilead Sciences Research Scholars Program in Cardiovascular Disease. J.M. was supported by NIH K08 HL097031, Heart Failure Society of America Research Fellowship, and the Watkins Cardiovascular Discovery Award (BWH). A.H.B. was supported by a grant from the Sarnoff Cardiovascular Research Foundation. A.A.C. was supported by grants from the “Friends of Dana-Farber” and the NIH T32CA009361. A.J.W. received grant support from NIH UO1 HL100402. M.G.V.H. was supported by the Broad Institute SPARC program and the Burrough’s Wellcome Fund. A.J.W. was supported by a grant from the NIH. A.K. was funded by NIH R01 CA157971, E.A.H. by F31 award (CA177119). W.G.K. was supported by grants from the NIH and is an HHMI Investigator. W.G.K. has a financial interest in Fibrogen, Inc., which is developing EGLN inhibitors for treating anemia and ischemic diseases.

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

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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 - Pierce, Kerry A.

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AU - Hanse, Eric A.

AU - Kelekar, Ameeta

AU - Sullivan, Lucas B.

AU - Wagers, Amy J.

AU - Clish, Clary B.

AU - Vander Heiden, Matthew G.

AU - Kaelin, William 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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