title: JMJD8 Regulates Angiogenic Sprouting and Cellular Metabolism by Interacting With Pyruvate Kinase M2 in Endothelial Cells.
abstract: Jumonji C (JmjC) domain-containing proteins modify histone and nonhistone proteins thereby controlling cellular functions. However, the role of JmjC proteins in angiogenesis is largely unknown. Here, we characterize the expression of JmjC domain-containing proteins after inducing endothelial differentiation of murine embryonic stem cells and study the function of JmjC domain-only proteins in endothelial cell (EC) functions.
  
  
  
  We identified a large number of JmjC domain-containing proteins regulated by endothelial differentiation of murine embryonic stem cells. Among the family of JmjC domain-only proteins, Jmjd8 was significantly upregulated on endothelial differentiation. Knockdown of Jmjd8 in ECs significantly decreased in vitro network formation and sprouting in the spheroid assay. JMJD8 is exclusively detectable in the cytoplasm, excluding a function as a histone-modifying enzyme. Mass spectrometry analysis revealed JMJD8-interacting proteins with known functions in cellular metabolism like pyruvate kinase M2. Accordingly, knockdown of pyruvate kinase M2 in human umbilical vein ECs decreased endothelial sprouting in the spheroid assay. Knockdown of JMJD8 caused a reduction of EC metabolism as measured by Seahorse Bioscience extracellular flux analysis. Conversely, overexpression of JMJD8 enhanced cellular oxygen consumption rate of ECs, reflecting an increased mitochondrial respiration.
  
  
  
  Jmjd8 is upregulated during endothelial differentiation and regulates endothelial sprouting and metabolism by interacting with pyruvate kinase M2.
authors.affiliation: From the Institute for Cardiovascular Regeneration, University Frankfurt, Frankfurt, Germany (J.-N.B., A.D., S.F.G., A.L., T.L., A.W.H., C.M.Z., D.K., A.D., K.O., K.T., S.D.); Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany (M.K.); Department of Cardiology, Internal Medicine III, Goethe-University Hospital, Frankfurt, Germany (C.M.Z.); and German Center of Cardiovascular Research (DZHK), RheinMain, Frankfurt, Germany (J.-N.B., A.D., S.F.G., T.L., C.M.Z., A.D., S.D.).
authors.forename: Jes-Niels
authors.initials: JN
authors.lastname: Boeckel
authors.affiliation: From the Institute for Cardiovascular Regeneration, University Frankfurt, Frankfurt, Germany (J.-N.B., A.D., S.F.G., A.L., T.L., A.W.H., C.M.Z., D.K., A.D., K.O., K.T., S.D.); Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany (M.K.); Department of Cardiology, Internal Medicine III, Goethe-University Hospital, Frankfurt, Germany (C.M.Z.); and German Center of Cardiovascular Research (DZHK), RheinMain, Frankfurt, Germany (J.-N.B., A.D., S.F.G., T.L., C.M.Z., A.D., S.D.).
authors.forename: Anja
authors.initials: A
authors.lastname: Derlet
authors.affiliation: From the Institute for Cardiovascular Regeneration, University Frankfurt, Frankfurt, Germany (J.-N.B., A.D., S.F.G., A.L., T.L., A.W.H., C.M.Z., D.K., A.D., K.O., K.T., S.D.); Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany (M.K.); Department of Cardiology, Internal Medicine III, Goethe-University Hospital, Frankfurt, Germany (C.M.Z.); and German Center of Cardiovascular Research (DZHK), RheinMain, Frankfurt, Germany (J.-N.B., A.D., S.F.G., T.L., C.M.Z., A.D., S.D.).
authors.forename: Simone F
authors.initials: SF
authors.lastname: Glaser
authors.affiliation: From the Institute for Cardiovascular Regeneration, University Frankfurt, Frankfurt, Germany (J.-N.B., A.D., S.F.G., A.L., T.L., A.W.H., C.M.Z., D.K., A.D., K.O., K.T., S.D.); Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany (M.K.); Department of Cardiology, Internal Medicine III, Goethe-University Hospital, Frankfurt, Germany (C.M.Z.); and German Center of Cardiovascular Research (DZHK), RheinMain, Frankfurt, Germany (J.-N.B., A.D., S.F.G., T.L., C.M.Z., A.D., S.D.).
authors.forename: Annika
authors.initials: A
authors.lastname: Luczak
authors.affiliation: From the Institute for Cardiovascular Regeneration, University Frankfurt, Frankfurt, Germany (J.-N.B., A.D., S.F.G., A.L., T.L., A.W.H., C.M.Z., D.K., A.D., K.O., K.T., S.D.); Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany (M.K.); Department of Cardiology, Internal Medicine III, Goethe-University Hospital, Frankfurt, Germany (C.M.Z.); and German Center of Cardiovascular Research (DZHK), RheinMain, Frankfurt, Germany (J.-N.B., A.D., S.F.G., T.L., C.M.Z., A.D., S.D.).
authors.forename: Tina
authors.initials: T
authors.lastname: Lucas
authors.affiliation: From the Institute for Cardiovascular Regeneration, University Frankfurt, Frankfurt, Germany (J.-N.B., A.D., S.F.G., A.L., T.L., A.W.H., C.M.Z., D.K., A.D., K.O., K.T., S.D.); Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany (M.K.); Department of Cardiology, Internal Medicine III, Goethe-University Hospital, Frankfurt, Germany (C.M.Z.); and German Center of Cardiovascular Research (DZHK), RheinMain, Frankfurt, Germany (J.-N.B., A.D., S.F.G., T.L., C.M.Z., A.D., S.D.).
authors.forename: Andreas W
authors.initials: AW
authors.lastname: Heumüller
authors.affiliation: From the Institute for Cardiovascular Regeneration, University Frankfurt, Frankfurt, Germany (J.-N.B., A.D., S.F.G., A.L., T.L., A.W.H., C.M.Z., D.K., A.D., K.O., K.T., S.D.); Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany (M.K.); Department of Cardiology, Internal Medicine III, Goethe-University Hospital, Frankfurt, Germany (C.M.Z.); and German Center of Cardiovascular Research (DZHK), RheinMain, Frankfurt, Germany (J.-N.B., A.D., S.F.G., T.L., C.M.Z., A.D., S.D.).
authors.forename: Marcus
authors.initials: M
authors.lastname: Krüger
authors.affiliation: From the Institute for Cardiovascular Regeneration, University Frankfurt, Frankfurt, Germany (J.-N.B., A.D., S.F.G., A.L., T.L., A.W.H., C.M.Z., D.K., A.D., K.O., K.T., S.D.); Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany (M.K.); Department of Cardiology, Internal Medicine III, Goethe-University Hospital, Frankfurt, Germany (C.M.Z.); and German Center of Cardiovascular Research (DZHK), RheinMain, Frankfurt, Germany (J.-N.B., A.D., S.F.G., T.L., C.M.Z., A.D., S.D.).
authors.forename: Christoph M
authors.initials: CM
authors.lastname: Zehendner
authors.affiliation: From the Institute for Cardiovascular Regeneration, University Frankfurt, Frankfurt, Germany (J.-N.B., A.D., S.F.G., A.L., T.L., A.W.H., C.M.Z., D.K., A.D., K.O., K.T., S.D.); Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany (M.K.); Department of Cardiology, Internal Medicine III, Goethe-University Hospital, Frankfurt, Germany (C.M.Z.); and German Center of Cardiovascular Research (DZHK), RheinMain, Frankfurt, Germany (J.-N.B., A.D., S.F.G., T.L., C.M.Z., A.D., S.D.).
authors.forename: David
authors.initials: D
authors.lastname: Kaluza
authors.affiliation: From the Institute for Cardiovascular Regeneration, University Frankfurt, Frankfurt, Germany (J.-N.B., A.D., S.F.G., A.L., T.L., A.W.H., C.M.Z., D.K., A.D., K.O., K.T., S.D.); Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany (M.K.); Department of Cardiology, Internal Medicine III, Goethe-University Hospital, Frankfurt, Germany (C.M.Z.); and German Center of Cardiovascular Research (DZHK), RheinMain, Frankfurt, Germany (J.-N.B., A.D., S.F.G., T.L., C.M.Z., A.D., S.D.).
authors.forename: Anuradha
authors.initials: A
authors.lastname: Doddaballapur
authors.affiliation: From the Institute for Cardiovascular Regeneration, University Frankfurt, Frankfurt, Germany (J.-N.B., A.D., S.F.G., A.L., T.L., A.W.H., C.M.Z., D.K., A.D., K.O., K.T., S.D.); Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany (M.K.); Department of Cardiology, Internal Medicine III, Goethe-University Hospital, Frankfurt, Germany (C.M.Z.); and German Center of Cardiovascular Research (DZHK), RheinMain, Frankfurt, Germany (J.-N.B., A.D., S.F.G., T.L., C.M.Z., A.D., S.D.).
authors.forename: Kisho
authors.initials: K
authors.lastname: Ohtani
authors.affiliation: From the Institute for Cardiovascular Regeneration, University Frankfurt, Frankfurt, Germany (J.-N.B., A.D., S.F.G., A.L., T.L., A.W.H., C.M.Z., D.K., A.D., K.O., K.T., S.D.); Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany (M.K.); Department of Cardiology, Internal Medicine III, Goethe-University Hospital, Frankfurt, Germany (C.M.Z.); and German Center of Cardiovascular Research (DZHK), RheinMain, Frankfurt, Germany (J.-N.B., A.D., S.F.G., T.L., C.M.Z., A.D., S.D.).
authors.forename: Karine
authors.initials: K
authors.lastname: Treguer
authors.affiliation: From the Institute for Cardiovascular Regeneration, University Frankfurt, Frankfurt, Germany (J.-N.B., A.D., S.F.G., A.L., T.L., A.W.H., C.M.Z., D.K., A.D., K.O., K.T., S.D.); Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany (M.K.); Department of Cardiology, Internal Medicine III, Goethe-University Hospital, Frankfurt, Germany (C.M.Z.); and German Center of Cardiovascular Research (DZHK), RheinMain, Frankfurt, Germany (J.-N.B., A.D., S.F.G., T.L., C.M.Z., A.D., S.D.). dimmeler@em.uni-frankfurt.de.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Dimmeler
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002454:Cell Differentiation; D019069:Cell Respiration; D053595:Embryonic Stem Cells / Q000201:enzymology*; D066026:Endothelial Progenitor Cells / Q000201:enzymology*; D004734:Energy Metabolism; D057809:HEK293 Cells; D061307:Human Umbilical Vein Endothelial Cells / Q000201:enzymology*; D006801:Humans; D056484:Jumonji Domain-Containing Histone Demethylases / Q000235:genetics / Q000378:metabolism*; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008928:Mitochondria / Q000201:enzymology; D018919:Neovascularization, Physiologic; D010101:Oxygen Consumption; D011485:Protein Binding; D011770:Pyruvate Kinase / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D015398:Signal Transduction; D013963:Thyroid Hormones / Q000235:genetics / Q000378:metabolism*; D013997:Time Factors; D014162:Transfection; D015854:Up-Regulation; D000097810:Thyroid Hormone-Binding Proteins
chemical_list: D002352:Carrier Proteins; D056484:Jumonji Domain-Containing Histone Demethylases; D008565:Membrane Proteins; D011770:Pyruvate Kinase; D013963:Thyroid Hormones; D000097810:Thyroid Hormone-Binding Proteins; C000620515:JMJD8 protein, mouse
keywords: cell differentiation; cell plasticity; chromatin; endothelial cells; metabolism