title: Myeloid-Specific Deletion of Diacylglycerol Lipase α Inhibits Atherogenesis in ApoE-Deficient Mice.
abstract: BACKGROUND
  The endocannabinoid 2-arachidonoylglycerol (2-AG) is a known modulator of inflammation. Despite its high concentration in vascular tissue, the role of 2-AG in atherogenesis has not yet been examined.
  
  
  METHODS
  ApoE-deficient mice were sublethally irradiated and reconstituted with bone marrow from mice with a myeloid-specific knockout of the 2-AG synthesising enzyme diacylglycerol lipase α (Dagla) or control bone marrow with an intact 2-AG biosynthesis. After a cholesterol-rich diet for 8 weeks, plaque size and plaque morphology were examined in chimeric mice. Circulating inflammatory cells were assessed by flow cytometry. Aortic tissue and plasma levels of endocannabinoids were measured using liquid chromatography-multiple reaction monitoring.
  
  
  RESULTS
  Mice with Dagla-deficient bone marrow and circulating myeloid cells showed a significantly reduced plaque burden compared to controls. The reduction in plaque size was accompanied by a significantly diminished accumulation of both neutrophil granulocytes and macrophages in atherosclerotic lesions of Dagla-deficient mice. Moreover, CB2 expression and the amount of oxidised LDL within atherosclerotic lesions was significantly reduced. FACS analyses revealed that levels of circulating inflammatory cells were unaltered in Dagla-deficient mice.
  
  
  CONCLUSIONS
  Myeloid synthesis of the endocannabinoid 2-AG appears to promote vascular inflammation and atherogenesis. Thus, myeloid-specific disruption of 2-AG synthesis may represent a potential novel therapeutic strategy against atherosclerosis.
authors.affiliation: Klinik II für Innere Medizin, Universität Bonn, Bonn, Germany.
authors.forename: Julian
authors.initials: J
authors.lastname: Jehle
authors.affiliation: Massachusetts General Hospital, Center for Systems Biology, Boston, United States of America.
authors.forename: Friedrich Felix
authors.initials: FF
authors.lastname: Hoyer
authors.affiliation: Klinik II für Innere Medizin, Universität Bonn, Bonn, Germany.
authors.forename: Benedikt
authors.initials: B
authors.lastname: Schöne
authors.affiliation: Klinik II für Innere Medizin, Universität Bonn, Bonn, Germany.
authors.forename: Philipp
authors.initials: P
authors.lastname: Pfeifer
authors.affiliation: Klinik II für Innere Medizin, Universität Bonn, Bonn, Germany.
authors.forename: Katharina
authors.initials: K
authors.lastname: Schild
authors.affiliation: Institut für Molekulare Psychiatrie, Universität Bonn, Bonn, Germany.
authors.forename: Imke
authors.initials: I
authors.lastname: Jenniches
authors.affiliation: Institut für Physiologische Chemie, Johannes Gutenberg Universität Mainz, Mainz, Germany.
authors.forename: Laura
authors.initials: L
authors.lastname: Bindila
authors.affiliation: Institut für Physiologische Chemie, Johannes Gutenberg Universität Mainz, Mainz, Germany.
authors.forename: Beat
authors.initials: B
authors.lastname: Lutz
authors.affiliation: Institut für Klinische Chemie und Klinische Pharmakologie, Universität Bonn, Bonn, Germany.
authors.forename: Dieter
authors.initials: D
authors.lastname: Lütjohann
authors.affiliation: Institut für Molekulare Psychiatrie, Universität Bonn, Bonn, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Zimmer
authors.affiliation: Klinik II für Innere Medizin, Universität Bonn, Bonn, Germany.
authors.forename: Georg
authors.initials: G
authors.lastname: Nickenig
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics* / Q000378:metabolism; D050197:Atherosclerosis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D001794:Blood Pressure / Q000235:genetics; D006339:Heart Rate / Q000235:genetics; D008071:Lipoprotein Lipase / Q000235:genetics* / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D022423:Myeloid Cells / Q000378:metabolism* / Q000473:pathology; D058226:Plaque, Atherosclerotic / Q000473:pathology; D043885:Receptor, Cannabinoid, CB2 / Q000235:genetics / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism
chemical_list: D001057:Apolipoproteins E; D043885:Receptor, Cannabinoid, CB2; D013481:Superoxides; D008071:Lipoprotein Lipase