EGLN1 Inhibition and Rerouting of α-Ketoglutarate Suffice for Remote Ischemic Protection.
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Abstract | 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. |
Year of Publication | 2016
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Journal | Cell
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Volume | 164
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Issue | 5
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Pages | 884-95
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Date Published | 2016 Feb 25
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ISSN | 1097-4172
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URL | |
DOI | 10.1016/j.cell.2016.02.006
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PubMed ID | 26919427
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PubMed Central ID | PMC4819986
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Grant list | T32 GM007287 / GM / NIGMS NIH HHS / United States
R01 CA068490 / CA / NCI NIH HHS / United States
T32CA009361 / CA / NCI NIH HHS / United States
T32 GM007753 / GM / NIGMS NIH HHS / United States
CA177119 / CA / NCI NIH HHS / United States
R01 CA157971 / CA / NCI NIH HHS / United States
U01 HL100402 / HL / NHLBI NIH HHS / United States
Howard Hughes Medical Institute / United States
K08 HL119355 / HL / NHLBI NIH HHS / United States
F31 CA177119 / CA / NCI NIH HHS / United States
F30 CA192725 / CA / NCI NIH HHS / United States
K08 HL097031 / HL / NHLBI NIH HHS / United States
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