Apolipoprotein A-I gene transfer exerts immunomodulatory effects and reduces vascular inflammation and fibrosis in ob/ob mice

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. © 2016 the author(s).