title: Apolipoprotein A-I gene transfer exerts immunomodulatory effects and reduces vascular inflammation and fibrosis in ob/ob mice.
abstract: BACKGROUND
  Obesity is associated with vascular inflammation, fibrosis and reduced high-density lipoproteins (HDL)-cholesterol. We aimed to investigate whether adenoviral gene transfer with human apolipoprotein (apo) A-I (Ad.A-I), the main apo of HDL, could exert immunomodulatory effects and counteract vascular inflammation and fibrosis in ob/ob mice.
  
  
  METHODS
  Ad.A-I transfer was performed in 8 weeks (w) old ob/ob mice, which were sacrificed 7 w later. The aorta was excised for mRNA analysis and the spleen for splenocyte isolation for subsequent flow cytometry and co-culture with murine fibroblasts. HDL was added to mononuclear cells (MNC) and fibroblasts to assess their impact on adhesion capacity and collagen deposition, respectively.
  
  
  RESULTS
  Ad.A-I led to a 1.8-fold (p < 0.05) increase in HDL-cholesterol versus control ob/ob mice at the day of sacrifice, which was paralleled by a decrease in aortic TNF-α and VCAM-1 mRNA expression. Pre-culture of MNC with HDL decreased their adhesion to TNF-α-activated HAEC. Ad.A-I exerted immunomodulatory effects as evidenced by a downregulation of aortic NOD2 and NLRP3 mRNA expression and by a 12 %, 6.9 %, and 15 % decrease of the induced proliferation/activity of total splenic MNC, CD4+, and CD8+ cells in ob/ob Ad.A-I versus control ob/ob mice, respectively (p < 0.05). Ad.A-I further reduced aortic collagen I and III mRNA expression by 62 % and 66 %, respectively (p < 0.0005), and abrogated the potential of ob/ob splenocytes to induce the collagen content in murine fibroblasts upon co-culture. Finally, HDL decreased the TGF-ß1-induced collagen deposition of murine fibroblasts in vitro.
  
  
  CONCLUSIONS
  Apo A-I transfer counteracts vascular inflammation and fibrosis in ob/ob mice.
authors.affiliation: Department of Cardiology, Charité-University-Medicine Berlin, Campus Virchow Klinikum (CVK), Berlin, Germany.
authors.forename: Frank
authors.initials: F
authors.lastname: Spillmann
authors.affiliation: Catholic University of Leuven, Center for Molecular and Vascular Biology, Department of Cardiovascular Sciences, Leuven, Belgium.
authors.forename: Bart
authors.initials: B
authors.lastname: De Geest
authors.affiliation: Catholic University of Leuven, Center for Molecular and Vascular Biology, Department of Cardiovascular Sciences, Leuven, Belgium.
authors.forename: Ilayaraja
authors.initials: I
authors.lastname: Muthuramu
authors.affiliation: Catholic University of Leuven, Center for Molecular and Vascular Biology, Department of Cardiovascular Sciences, Leuven, Belgium.
authors.forename: Ruhul
authors.initials: R
authors.lastname: Amin
authors.affiliation: Berlin-Brandenburg Center for Regenerative Therapy (BCRT), Charité-University-Medicine Berlin, Campus Virchow Klinikum (CVK), Südstrasse 2, 13353 Berlin, Germany.
authors.forename: Kapka
authors.initials: K
authors.lastname: Miteva
authors.affiliation: Department of Cardiology, Charité-University-Medicine Berlin, Campus Virchow Klinikum (CVK), Berlin, Germany ; Deutsches Zentrum für Herz Kreislaufforschung (DZHK), Standort Berlin/Charité, Berlin, Germany ; Department of Cardiology, Deutsches Herzzentrum Berlin (DHZB), Berlin, Germany.
authors.forename: Burkert
authors.initials: B
authors.lastname: Pieske
authors.affiliation: Department of Cardiology, Charité-University-Medicine Berlin, Campus Virchow Klinikum (CVK), Berlin, Germany ; Berlin-Brandenburg Center for Regenerative Therapy (BCRT), Charité-University-Medicine Berlin, Campus Virchow Klinikum (CVK), Südstrasse 2, 13353 Berlin, Germany ; Deutsches Zentrum für Herz Kreislaufforschung (DZHK), Standort Berlin/Charité, Berlin, Germany.
authors.forename: Carsten
authors.initials: C
authors.lastname: Tschöpe
authors.affiliation: Department of Cardiology, Charité-University-Medicine Berlin, Campus Virchow Klinikum (CVK), Berlin, Germany ; Berlin-Brandenburg Center for Regenerative Therapy (BCRT), Charité-University-Medicine Berlin, Campus Virchow Klinikum (CVK), Südstrasse 2, 13353 Berlin, Germany ; Deutsches Zentrum für Herz Kreislaufforschung (DZHK), Standort Berlin/Charité, Berlin, Germany.
authors.forename: Sophie
authors.initials: S
authors.lastname: Van Linthout
keywords: Aorta; HDL; Immunomodulation; Vascular fibrosis