title: EGLN1 Inhibition and Rerouting of α-Ketoglutarate Suffice for Remote Ischemic Protection.
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.
authors.affiliation: 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.
authors.forename: Benjamin A
authors.initials: BA
authors.lastname: Olenchock
authors.affiliation: Division of Cardiovascular Medicine, Department of Medicine, Vanderbilt School of Medicine, Nashville, TN 37235, USA.
authors.forename: Javid
authors.initials: J
authors.lastname: Moslehi
authors.affiliation: Department of Medicine, University of California, San Francisco, San Francisco, CA 94117, USA.
authors.forename: Alan H
authors.initials: AH
authors.lastname: Baik
authors.affiliation: Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
authors.forename: Shawn M
authors.initials: SM
authors.lastname: Davidson
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
authors.forename: Jeremy
authors.initials: J
authors.lastname: Williams
authors.affiliation: Harvard Medical School, Boston, MA 02115, USA; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
authors.forename: William J
authors.initials: WJ
authors.lastname: Gibson
authors.forename: Abhishek A
authors.initials: AA
authors.lastname: Chakraborty
authors.affiliation: Metabolomics Platform, Broad Institute, Cambridge, MA 02142, USA.
authors.forename: Kerry A
authors.initials: KA
authors.lastname: Pierce
authors.affiliation: Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA; Joslin Diabetes Center, Boston, MA 02215, USA.
authors.forename: Christine M
authors.initials: CM
authors.lastname: Miller
authors.affiliation: Department of Laboratory Medicine and Pathology and Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA.
authors.forename: Eric A
authors.initials: EA
authors.lastname: Hanse
authors.affiliation: Department of Laboratory Medicine and Pathology and Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA.
authors.forename: Ameeta
authors.initials: A
authors.lastname: Kelekar
authors.affiliation: Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
authors.forename: Lucas B
authors.initials: LB
authors.lastname: Sullivan
authors.affiliation: Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA; Joslin Diabetes Center, Boston, MA 02215, USA.
authors.forename: Amy J
authors.initials: AJ
authors.lastname: Wagers
authors.affiliation: Metabolomics Platform, Broad Institute, Cambridge, MA 02142, USA.
authors.forename: Clary B
authors.initials: CB
authors.lastname: Clish
authors.affiliation: 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.
authors.forename: Matthew G
authors.initials: MG
authors.lastname: Vander Heiden
authors.affiliation: 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.
authors.forename: William G
authors.initials: WG
authors.lastname: Kaelin
mesh_terms: D000818:Animals; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases / Q000037:antagonists & inhibitors*; D007511:Ischemia / Q000517:prevention & control; D019194:Ischemic Preconditioning; D007656:Ketoglutaric Acids / Q000378:metabolism*; D007736:Kynurenic Acid / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D051379:Mice; D023421:Models, Animal; D015428:Myocardial Reperfusion Injury / Q000517:prevention & control; D010227:Parabiosis
chemical_list: D007656:Ketoglutaric Acids; C490189:Egln1 protein, mouse; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases; D007736:Kynurenic Acid