Journal
CELL
Volume 164, Issue 5, Pages 884-895Publisher
CELL PRESS
DOI: 10.1016/j.cell.2016.02.006
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Categories
Funding
- NIH [K08 HL119355, K08 HL097031, UO1 HL100402, R01 CA157971]
- Gilead Sciences Research Scholars Program in Cardiovascular Disease
- Heart Failure Society of America Research Fellowship
- Watkins Cardiovascular Discovery Award
- Sarnoff Cardiovascular Research Foundation
- Broad Institute SPARC program
- Burrough's Wellcome Fund
- F31 award [CA177119]
- Fibrogen, Inc.
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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 (alpha KG)-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 alpha KG, 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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