Abstract
BackgroundRP105 (CD180) is TLR4 homologue lacking the intracellular TLR4 signaling domain and acts a TLR accessory molecule and physiological inhibitor of TLR4-signaling. The role of RP105 in vascular remodeling, in particular post-interventional remodeling is unknown.Methods and ResultsTLR4 and RP105 are expressed on vascular smooth muscle cells (VSMC) as well as in the media of murine femoral artery segments as detected by qPCR and immunohistochemistry. Furthermore, the response to the TLR4 ligand LPS was stronger in VSMC from RP105−/− mice resulting in a higher proliferation rate. In RP105−/− mice femoral artery cuff placement resulted in an increase in neointima formation as compared to WT mice (4982±974 µm2 vs.1947±278 µm2,p = 0.0014). Local LPS application augmented neointima formation in both groups, but in RP105−/− mice this effect was more pronounced (10316±1243 µm2 vs.4208±555 µm2,p = 0.0002), suggesting a functional role for RP105. For additional functional studies, the extracellular domain of murine RP105 was expressed with or without its adaptor protein MD1 and purified. SEC-MALSanalysis showed a functional 2∶2 homodimer formation of the RP105-MD1 complex. This protein complex was able to block the TLR4 response in whole blood ex-vivo. In vivo gene transfer of plasmid vectors encoding the extracellular part of RP105 and its adaptor protein MD1 were performed to initiate a stable endogenous soluble protein production. Expression of soluble RP105-MD1 resulted in a significant reduction in neointima formation in hypercholesterolemic mice (2500±573 vs.6581±1894 µm2,p<0.05), whereas expression of the single factors RP105 or MD1 had no effect.ConclusionRP105 is a potent inhibitor of post-interventional neointima formation.
Highlights
In interventional cardiology restenosis remains a critical determinant of long-term efficacy of Percutaneous Coronary Interventions (PCI)
RP105 is a potent inhibitor of post-interventional neointima formation
In the current study we demonstrate a functional role for RP105 in vascular remodeling during neointimal formation by the use knockout mice, cultured vascular smooth muscle cells (VSMC), purified proteins and by in vivo gene transfer mediated overexpression of soluble RP105 protein combined with the MD1 accessory protein
Summary
In interventional cardiology restenosis remains a critical determinant of long-term efficacy of Percutaneous Coronary Interventions (PCI). Neointima formation is a common feature of restenosis and atherosclerosis and is characterized by proliferation and migration of vascular smooth muscle cells (VSMC) and extracellular matrix formation [1,2]. These processes are strongly mediated by inflammation and influx of inflammatory cells in the affected vessel wall [3]. LPS initiates TLR4 activation and the resulting inflammatory reaction causes a release of many proinflammatory cytokines that will affect the pathophysiological process of neointima formation strongly [7,8]. The role of RP105 in vascular remodeling, in particular postinterventional remodeling is unknown
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