Abstract 370: Interferon Regulatory Factors 3 and 7 Regulate Vein Graft Remodeling and Vascular Inflammation

Introduction: Type I interferons (IFN) are implicated in the development of vascular proliferative diseases. Pathway analysis by gene set enrichment analysis of hypercholesterolemic ApoE3*Leiden murine vein grafts revealed that the type I IFN pathway belonged to the top 15 of significant regulated pathways. The transcriptional regulators of type I IFN and type I IFN responsive genes are the interferon regulatory factors (IRF). Activation of TLR3 results in activation of type I IFN in a IRF3 and IRF7 dependent manner. TLR3 has been shown to be protective in vascular remodeling. The aim of this study was to investigate the role of IRF3 and IRF7 on vein graft remodeling. Methods and Results: The importance of IRFs in vein graft remodeling is illustrated by the increase in vein graft thickening in Irf3 -/- and Irf7 -/- mice in comparison to control mice (n=9/group, Irf3 -/- ; 39%, p=0.185, Irf7 -/- ; 68% p=0.003). Also an increase in outward remodeling ( Irf3 -/- ; 26%, p=0.081, Irf7 -/- ; 42%, p=0.049) was observed comparable to that of Tlr3 -/- (n=8, 52%, p<0.001) Immunohistochemical analysis revealed that both Irf3 -/- and Irf7 -/- mice showed a significant higher influx of macrophages in the vessel wall than the control mice whereas the Irf7 -/- mice also showed a significant decrease in collagen content. RNA levels of typical type I IFN responsive genes such as Mx1, Ifit1-3 and Oas2 were down regulated in the knockout vein grafts in comparison to control vein grafts. Activation of both Irf3 -/- and Irf7 -/- bone marrow derived macrophages with LPS and poly:(IC) resulted in a significant increase in TNFα production. Conclusions: IRFs regulates vein graft remodeling since Irf3 -/- and especially Irf7 -/- vein grafts show increased vessel wall thickening and outward remodeling. This increased remodeling is the result of a pro-inflammatory response as reflected by the increase in macrophages in the vein graft wall.