Objective-Clinical studies have identified that reduced numbers of circulating plasmacytoid dendritic cells (pDCs) act as a predictor of cardiovascular events in coronary artery disease and that pDCs are detectable in the shoulder region of human atherosclerotic plaques, where rupture is most likely to occur. Results from animal models are controversial, with pDCs seen to inhibit or promote lesion development depending on the experimental settings. Here, we investigated the role of pDCs in atherosclerosis in apolipoprotein E−deficient mice. Methods and Results-We demonstrated that the aorta and spleen of both apolipoprotein E−deficient and C57BL/6 mice displayed similar numbers of pDCs, with similar activation status. In contrast, assessment of antigen uptake/presentation using the Eα/Y-Ae system revealed that aortic pDCs in apolipoprotein E−deficient -mice were capable of presenting in vivo systemically administered antigen. Continuous treatment of apolipoprotein E−deficient mice with anti−mouse plasmacytoid dendritic cell antigen 1 (mPDCA-1) antibody caused specific depletion of pDCs in the aorta and spleen and significantly reduced atherosclerosis formation in the aortic sinus (by 46%; P<0.001). Depletion of pDCs also reduced macrophages (by 34%; P<0.05) and increased collagen content (by 41%; P<0.05) in aortic plaques, implying a more stable plaque phenotype. Additionally, pDC depletion reduced splenic T-cell activation and inhibited interleukin-12, chemokine (C-X-C motif) ligand 1, monokine induced by interferon-γ, interferon γ−induced protein 10, and vascular endothelium growth factor serum levels. Conclusion-These
T he pathogenesis of postangioplasty restenosis involves migration and proliferation of vascular smooth muscle cells (VSMCs), which constitute a major component of postangioplasty neointimal lesions.1-4 VSMC migration and proliferation are regulated by growth factors, adhesion molecules, proteases, and intracellular proteins. Among them, the cadherin-β-catenin complex and its cognate intracellular pathway have been increasingly appreciated as important regulators of these processes. 5-8Matrix metalloproteinase-8 (MMP8) was once thought to be produced exclusively by polymorphonuclear leukocytes, but more recent studies have shown that various other cell types including stem/progenitor cells express this protease.9 Compared with some other members of the MMP family, MMP8 has been less investigated for its proteolytic substrates and biological roles. Herman et al 10 were the first to reveal that VSMCs, endothelial cells, and macrophages in atherosclerotic plaques express MMP8. Subsequently other investigators showed a correlation between increased MMP8 expression and rapid atherosclerotic lesion progression.11,12 A causal role of MMP8 in atherosclerosis development was demonstrated by our recent study, which showed that in apolipoprotein E (apoE)-deficient mice fed a Western diet for 12 weeks, MMP8 knockout resulted in a significant reduction of atherosclerotic lesions with decreased macrophage and VSMC contents. 13 The study also revealed a role of MMP8 in vascular recruitment of leukocytes, 13 providing a mechanistic explanation for the effect of MMP8 knockout on macrophage content in atherosclerotic lesions.In the present study, we sought to investigate whether MMP8 also plays a role in neointima formation after vessel © 2013 American Heart Association, Inc. Objective-We investigated the role of matrix metalloproteinase-8 (MMP8) in neointima formation and in vascular smooth muscle cell (VSMC) migration and proliferation. Approach and Results-After carotid artery wire injuring, MMP8-/-/apoE -/-mice had fewer proliferating cells in neointimal lesions and smaller lesion sizes. Ex vivo assays comparing VSMCs isolated from MMP8 knockout and wild-type mice showed that MMP8 knockout decreased proliferation and migration. Proteomics analysis revealed that a disintegrin and metalloproteinase domain-containing protein 10 (ADAM10) had lower concentrations in MMP8 knockout VSMC culture media than in MMP8 wild-type VSMC culture media. Western blot, flow cytometric, and immunocytochemical analyses showed that MMP8 knockout VSMCs contained more pro-ADAM10 but less mature ADAM10, more N-cadherin, and β-catenin in the plasma membrane but less β-catenin in the nucleus and less cyclin D1. Treatment of MMP8 wildtype VSMCs with an ADAM10 inhibitor, GI254023X, or siRNA knockdown of ADAM10 in MMP8 wild-type VSMCs inhibited proliferation and migration, increased N-cadherin and β-catenin in the plasma membrane, reduced β-catenin in the nucleus, and decreased cyclin D1 expression. Incubation of MMP8 knockout VSMCs with a recombinant ADAM...
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