title: Role of extracellular RNA in atherosclerotic plaque formation in mice.
abstract: BACKGROUND
  Atherosclerosis and vascular remodeling after injury are driven by inflammation and mononuclear cell infiltration. Extracellular RNA (eRNA) has recently been implicated to become enriched at sites of tissue damage and to act as a proinflammatory mediator. Here, we addressed the role of eRNA in high-fat diet-induced atherosclerosis and neointima formation after injury in atherosclerosis-prone mice.
  
  
  RESULTS
  The presence of eRNA was revealed in atherosclerotic lesions from high-fat diet-fed low-density lipoprotein receptor-deficient (Ldlr(-/-)) mice in a time-progressive fashion. RNase activity in plasma increased within the first 2 weeks (44±9 versus 70±7 mU/mg protein; P=0.0012), followed by a decrease to levels below baseline after 4 weeks of high-fat diet (44±9 versus 12±2 mU/mg protein; P<0.0001). Exposure of bone marrow-derived macrophages to eRNA resulted in a concentration-dependent upregulation of the proinflammatory mediators tumor necrosis factor-α, arginase-2, interleukin-1β, interleukin-6, and interferon-γ. In a model of accelerated atherosclerosis after arterial injury in apolipoprotein E-deficient (ApoE(-/-)) mice, treatment with RNase1 diminished the increased plasma level of eRNA evidenced after injury. Likewise, RNase1 administration reduced neointima formation in comparison with vehicle-treated ApoE(-/-) controls (25.0±6.2 versus 46.9±6.9×10(3) μm(2), P=0.0339) and was associated with a significant decrease in plaque macrophage content. Functionally, RNase1 treatment impaired monocyte arrest on activated smooth muscle cells under flow conditions in vitro and inhibited leukocyte recruitment to injured carotid arteries in vivo.
  
  
  CONCLUSIONS
  Because eRNA is associated with atherosclerotic lesions and contributes to inflammation-dependent plaque progression in atherosclerosis-prone mice, its targeting with RNase1 may serve as a new treatment option against atherosclerosis.
authors.affiliation: Institute for Molecular Cardiovascular Research, RWTH University Hospital Aachen, Aachen, Germany (S.S., E.A.L.); Department of Biochemistry, Medical School, Justus-Liebig-University, Giessen, Germany (H.A.C.-F., K.T.P.); Department of Microbiology, Kazan Federal University, Kazan, Russian Federation (H.A.C.-F.); Center for Cardiovascular Research, John A. Burns School of Medicine, University of Hawaii, Honolulu, HI (S.M., Y.B., W.A.B.); Core Lab for Molecular and Structural Biology, Max-Planck-Institute for Heart and Lung Research, Bad Nauheim, Germany (S.K.); Institute for Cardiovascular Prevention, Ludwig-Maximilians-University, Munich, Germany (C.W.); DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, Munich, Germany (C.W., A.Z.); Rudolf Virchow Center and Institute of Clinical Biochemistry and Pathobiochemistry, University Hospital Würzburg, University of Würzburg, Würzburg, Germany (A.Z.); and Department of Vascular Surgery, Klinikum rechts der Isar, Technical University, Munich, Germany (A.Z.).
authors.forename: Sakine
authors.initials: S
authors.lastname: Simsekyilmaz
authors.forename: Hector A
authors.initials: HA
authors.lastname: Cabrera-Fuentes
authors.forename: Svenja
authors.initials: S
authors.lastname: Meiler
authors.forename: Sawa
authors.initials: S
authors.lastname: Kostin
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Baumer
authors.forename: Elisa A
authors.initials: EA
authors.lastname: Liehn
authors.forename: Christian
authors.initials: C
authors.lastname: Weber
authors.forename: William A
authors.initials: WA
authors.lastname: Boisvert
authors.forename: Klaus T
authors.initials: KT
authors.lastname: Preissner
authors.forename: Alma
authors.initials: A
authors.lastname: Zernecke
mesh_terms: D000818:Animals; D050197:Atherosclerosis / Q000097:blood / Q000139:chemically induced / Q000188:drug therapy; D059305:Diet, High-Fat / Q000009:adverse effects; D045604:Extracellular Fluid / Q000201:enzymology / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D058226:Plaque, Atherosclerotic / Q000097:blood* / Q000139:chemically induced / Q000188:drug therapy; D012313:RNA / Q000097:blood / Q000502:physiology*; D012260:Ribonucleases / Q000502:physiology* / Q000627:therapeutic use
chemical_list: D012313:RNA; D012260:Ribonucleases
keywords: atherosclerosis; inflammation; nucleic acids; vascular diseases