Abstract 15141: The TLR3 Pathway Including Downstream Interferon Regulating Factors, Regulates Vein Graft Remodeling
INTRODUCTION: Most Toll like receptors (TLRs) augment vein graft thickening and remodeling via MyD88 dependent induction of inflammatory cytokines. TLR3 is unique among the TLRs since signalling occurs in a MyD88 independent manner (via activation of TRIF and key interferon regulating factors, IRF3 and IRF7) resulting in induction of type I interferons. The aim of this study was to investigate the role of TLR3 pathway constituents on vein graft remodelling.
Methods and Results: Pathway analysis by GSEA using curated genesets and canonical pathways was performed on a gene array dataset (Illumina MouseWG-6) generated from a time course of vein grafts (t0, t3, t7, t14 and t28) in hypercholesterolemic ApoE3Leiden mice. This GSEA analysis revealed that at all time points, in comparison to non-injured caval veins (t0), the TLR pathway as well as the type I Interferon pathway belonged to the top 40 of significant regulated pathways. The importance of the type I Interferon pathway is further illustrated by the 2-fold increase in vein graft thickening in Tlr3-/- mice compared to control mice (p<0.001). Also Irf3-/- and Irf7-/- mice showed increased vein graft thickening (Irf3-/-; 39%, p=0.185, Irf7-/-; 68% p=0.003). No differences in lumen area were found, whereas total vein graft areas were increased compared to control mice, therefore all three strains showed outward remodeling (Tlr3-/-; 52%, p<0.001, Irf3-/-; 26%, p=0.081, Irf7-/-; 42%, p=0.049). Morphologic analysis revealed that Tlr3-/-, Irf3-/- and Irf7-/- mice showed significant more influx of macrophages than the control mice. The relative percentage smooth muscle cells and collagen in the vein graft walls did not deviate between the three strains and controls. RNA levels of TNFα and CCL2 were significantly increased in the Tlr3-/- mice, whereas Irf3-/- and Irf7-/- mice showed no increases in gene expression compared to controls.
Conclusions: The TLR3 pathway regulates for vein graft remodeling since Tlr3-/-, as well as the key downstream factors Irf3-/- and Irf7-/- vein grafts show increased vessel wall thickening and outward remodeling. This increased remodeling in the knock out mice is the result of a pro-inflammatory response as reflected by the increase in macrophages and cytokines in the vein graft wall.
- © 2013 by American Heart Association, Inc.