Abstract 10648: Matrix Metalloproteinase-8 Promotes Vascular Smooth Muscle Cell Proliferation and Neointima Formation

BACKGROUND: The pathogenesis of atherosclerosis and post-angioplasty restenosis involves migration and proliferation of vascular smooth muscle cells (VSMCs) which constitute a major component of atherosclerotic plaques and post-angioplasty neointimal lesions. However, the underlying molecular mechanisms of VSMC proliferation and proliferation are currently incompletely elucidated. Objective: We investigated effect of matrix metalloproteinase-8 (MMP8) on VSMC proliferation in the context of atherosclerosis and neointima formation. Methods and Results: Analyses of MMP8 -/- /apoE -/- and MMP8 +/+ /apoE -/- mice fed a Western diet showed that MMP8 knockout mice had smaller aortic root atherosclerotic lesions with fewer proliferating VSMCs. Following 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 wildtype mice showed that MMP8 knockout decreased proliferation. Proteomics analysis revealed that ADAM10 (a-disintegrin-and-metalloproteinase-domain-containing-protein 10) had lower concentrations in MMP8 knockout VSMC culture media than in MMP8 wildtype 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, inhibited proliferation, increased N-cadherin and β-catenin in the plasma membrane, reduced β-catenin in the nucleus, and decreased cyclin D1 expression. Conclusions: MMP8 enhances VSMC proliferation via an ADAM10, N-cadherin and β-catenin mediated pathway, and plays an important role in atherosclerosis progression and in neointima formation.