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EGLN1 Inhibition and Rerouting of α-Ketoglutarate Suffice for Remote Ischemic Protection.
Olenchock, Benjamin A; Moslehi, Javid; Baik, Alan H; Davidson, Shawn M; Williams, Jeremy; Gibson, William J; Chakraborty, Abhishek A; Pierce, Kerry A; Miller, Christine M; Hanse, Eric A; Kelekar, Ameeta; Sullivan, Lucas B; Wagers, Amy J; Clish, Clary B; Vander Heiden, Matthew G; Kaelin, William G.
  • Olenchock BA; 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.
  • Moslehi J; Division of Cardiovascular Medicine, Department of Medicine, Vanderbilt School of Medicine, Nashville, TN 37235, USA.
  • Baik AH; Department of Medicine, University of California, San Francisco, San Francisco, CA 94117, USA.
  • Davidson SM; Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
  • Williams J; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
  • Gibson WJ; Harvard Medical School, Boston, MA 02115, USA; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
  • Pierce KA; Metabolomics Platform, Broad Institute, Cambridge, MA 02142, USA.
  • Miller CM; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA; Joslin Diabetes Center, Boston, MA 02215, USA.
  • Hanse EA; Department of Laboratory Medicine and Pathology and Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA.
  • Kelekar A; Department of Laboratory Medicine and Pathology and Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA.
  • Sullivan LB; Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
  • Wagers AJ; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA; Joslin Diabetes Center, Boston, MA 02215, USA.
  • Clish CB; Metabolomics Platform, Broad Institute, Cambridge, MA 02142, USA.
  • Vander Heiden MG; 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.
  • Kaelin WG; 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.
Cell ; 164(5): 884-95, 2016 Feb 25.
Article en En | MEDLINE | ID: mdl-26919427
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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Texto completo: 1 Banco de datos: MEDLINE Asunto principal: Precondicionamiento Isquémico / Prolina Dioxigenasas del Factor Inducible por Hipoxia / Ácidos Cetoglutáricos Tipo de estudio: Prognostic_studies Límite: Animals Idioma: En Año: 2016 Tipo del documento: Article
Texto completo
Imprimir
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PubMed Links
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Texto completo: 1 Banco de datos: MEDLINE Asunto principal: Precondicionamiento Isquémico / Prolina Dioxigenasas del Factor Inducible por Hipoxia / Ácidos Cetoglutáricos Tipo de estudio: Prognostic_studies Límite: Animals Idioma: En Año: 2016 Tipo del documento: Article