Abstract 14280: RP105, a Toll Like Receptor 4 (TLR4) homolog, moderates restenosis and outward remodeling.
Introduction: RP105, a homolog of TLR4, is a physiological endogenous inhibitor of TLR4 signaling. Previously, we and others have shown that TLR4 is involved in restenosis, vein graft disease and accelerated atherosclerosis. A role for RP105 in cardiovascular disease has not been described yet.
Hypothesis: We hypothesize that RP105 modulates restenosis and outward remodeling via inhibition of TLR4 signaling.
Methods and Results: Genotyping for 10 SingleNucleotidePolymorphisms (SNPs) in the RP105 gene was performed in 866 patients from the GENetic DEterminants of Restenosis (GENDER) population, comprising of patients treated successfully by PCI with a 9 month follow-up for death, MI and target vessel revascularization. One specific RP105 SNP associated with a significantly reduced risk for restenosis (rs5744478, odds ratio 0.59, p=0.013). Femoral artery cuff placement was used as a murine model for restenosis in either wildtype (WT), RP105−/− or hypercholesterolemic APOE*3Leiden mice. Mice were sacrificed at 3 weeks or as stated otherwise. Cuff placement in RP105−/− mice resulted a strong increase in neoinitma formation compared to the WT mice (4982 μm2 (n=8) vs 1947 μm2 (n=9), p=0.0014). Local, TLR4 ligand, LPS application (1 μg/μL in pluronic gel) caused a profound increase in neointima formation in both groups (RP105−/− (n=9) vs WT (n=8) and again stronger neointima formation was seen in RP105−/− (10316μm2 vs 4208 μm2, p=0.0002). Furthermore local LPS application initiated outward remodeling in the RP105−/− mice (33315 μm2 vs 21401 μm2, p=0.027), an effect not seen in the absence of LPS. Expression of RP105 during neointima formation was studied in hypercholesterolemic APOE*3Leiden mice, at t=1, 3, 7 and 14d after cuff placement. RP105 was detected by immunohistochemistry on cross sections of cuffed femoral arteries. RP105 expression was observed during the whole remodeling process especially in the SMCs in the vessel wall.
In Conclusion:, an association of a RP105 specific SNP with human restenosis, the presence of RP105 in murine arteries in time and the increased restenosis in RP105−/− mice indicate RP105 as mediator of restenosis. Most likely RP105 modulates the TLR4 driven vascular remodeling and therefore is an interesting new target for therapy.
- © 2010 by American Heart Association, Inc.