Abstract 14625: Tlr7/9 Activation Enhances Neointima Formation in Hypercholesterolemic Apoe*3Leiden Mice
Introduction A functional role for the cell surface TLRs 2 and 4 in vascular remodeling during restenosis, vein graft disease and accelerated atherosclerosis is well established. However a role of intracellular TLRs 7 and 9 in restenosis and accelerated atherosclerosis is still unknown. In the current study we analyzed the role of TLR7and 9 activation in intimal hyperplasia in hypercholesterolemic mice.
Methods and Results TLR7 and TLR9 expression in cuffed femoral arteries was demonstrated by immunohistochemistry (IHC). Stimulation of bone marrow derived macrophages with TLR7/9 ligands enhanced TNFα expression and co-administration with a novel dual TLR7/9 antagonist decreased TNFα production. Furthermore lipid uptake could be initiated by co-administration of LDL with TLR7 ligand imiquimod which could be abolished by the antagonist. Moreover antagonist reduced lipid uptake of oxLDL by macrophages and increased production of IL10 (36.1±22.3pg vs. 128.9±6.6pg, p=0.008). Femoral artery cuff placement for 14 days induced neointima formation in hypercholesterolemic APOE*3Leiden mice which was decreased by administration of TLR7/9 antagonist biweekly (5838±1158µm2 vs. 2008±223µm2, p=0.0079). Accordingly a beneficial intima/media ratio (0.473±0.09µm2 vs. 0.168±0.018µm2, p=0.0021) and decreased percentage of luminal stenosis were observed (33.9±6.6% vs. 12.5±2.9%, p=0.0021). In addition less infiltration in the vessel wall of leukocytes and specifically macrophages was observed
In conclusion the presence of TLR7 and TLR9 expression in the neointimal lesions after cuff placement and the fact that a TLR7/9 antagonist strongly reduced lesion formation indicate the potential of TLR7/9 inhibition to prevent restenosis and accelerated atherosclerosis. These beneficial effects are most likely due to reduced macrophage activation and foam cell formation.
- © 2011 by American Heart Association, Inc.