Abstract 15552: Interferon Regulatory Factors 3 and 7 Regulate Vein Graft Remodeling via Tumor Necrosis Factor Induced Macrophage Accumulation
Introduction: Vein grafts are used to bypass atherosclerotic lesions; however, patency rates of these grafts are poor. Inflammation driven by toll like receptors (TLRs) is a major cause of vein graft failure. Interferon regulatory factors (IRF) 3 and 7 are transcription factors downstream TLR signaling, regulating type I interferons (IFN) and type I IFN responsive genes (IFNRS). Recent data indicate that type I IFN are necessary for sustaining tumor necrosis factor (TNF)-driven inflammation. Here we hypothesize that IRF3 and IRF7 play a causal role in vein graft remodeling via modulation of type I IFNs and subsequent modulation of TNF mediated macrophage accumulation.
Methods and Results: Male Irf3-/-, Irf7-/- and C57Bl/6 mice underwent vein graft surgery, by interpositioning of a donor vena cava in the art. carotis of a receiver mouse. In control vein grafts both IRF3 and IRF7 are expressed in inflammatory as well as vascular cells as shown by IHC. In Irf3-/- and Irf7-/- mice, compared to control, an increased vein graft thickening is observed 28d after surgery (n=9/group, Irf3-/- 39%, Irf7-/- 68%). At 28d both Irf3-/- and Irf7-/- mice showed a significant higher influx of macrophages in the vein graft compared to controls. At 28d IFNa4 and IFNb1 mRNA levels were detectable, but not differentially regulated. However, RNA levels of typical IFNRS such as Mx1, Ifit1-3 and Oas2 were down regulated in the knockout vein grafts compared to controls. Stimulation of both Irf3-/- and Irf7-/- bone marrow derived macrophages with the TLR ligand LPS, resulted in a significant increase in TNF production, compared to control. The early response of IRF3 and IRF7 was studied in vein grafts of Irf3-/- and Irf7-/- mice, harvested 7d after surgery. However, apart from an increased fibrin content in Irf3-/- mice (p=0.04) no differences in vein graft thickening or macrophage content of the vessel wall of Irf3-/- and Irf7-/- mice were seen.
Conclusions: The increased vessel wall thickening 28d after surgery observed in Irf3-/- and especially Irf7-/- vein grafts demonstrates that IRFs regulate vein graft remodeling, by late pro-inflammatory responses as reflected by altered TNF expression in Irf3-/- and Irf7-/- macrophages and altered accumulation of macrophages in the vein graft wall.
Author Disclosures: K.H. Simons: None. M.R. de Vries: None. E.A. Peters: None. J.F. Hamming: None. J.W. Jukema: None. P.H. Quax: None.
- © 2016 by American Heart Association, Inc.