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Cell. 2016 Feb 25;164(5):884-95. doi: 10.1016/j.cell.2016.02.006.

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

Author information

1
Division of Cardiovascular Medicine, Department of Medicine, The Brigham and Women's Hospital, Boston, MA 02115, USA; Harvard Medical School, Boston, MA 02115, USA; Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
2
Division of Cardiovascular Medicine, Department of Medicine, Vanderbilt School of Medicine, Nashville, TN 37235, USA.
3
Department of Medicine, University of California, San Francisco, San Francisco, CA 94117, USA.
4
Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
5
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
6
Harvard Medical School, Boston, MA 02115, USA; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
7
Metabolomics Platform, Broad Institute, Cambridge, MA 02142, USA.
8
Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA; Joslin Diabetes Center, Boston, MA 02215, USA.
9
Department of Laboratory Medicine and Pathology and Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA.
10
Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
11
Harvard Medical School, Boston, MA 02115, USA; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA. Electronic address: william_kaelin@dfci.harvard.edu.

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.

PMID:
26919427
PMCID:
PMC4819986
[Available on 2017-02-25]
DOI:
10.1016/j.cell.2016.02.006
[Indexed for MEDLINE]
Free PMC Article

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