Matrix metalloproteinase-8 promotes vascular smooth muscle cell proliferation and neointima formation

Xiao, Q. et al. (2014) Matrix metalloproteinase-8 promotes vascular smooth muscle cell proliferation and neointima formation. Arteriosclerosis, Thrombosis, and Vascular Biology, 34(1), pp. 90-98. (doi: 10.1161/ATVBAHA.113.301418) (PMID:24158518)

Abstract

OBJECTIVE: We investigated the role of matrix metalloproteinase-8 (MMP8) in neointima formation and in vascular smooth muscle cell (VSMC) migration and proliferation.<p></p> 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 wild-type 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 ADAM10 rescued the proliferative and migratory ability of MMP8 knockout VSMCs and increased cyclin D1 expression. Furthermore, immunohistochemical analyses showed colocalization of ADAM10 with VSMCs and N-cadherin, and nuclear accumulation of β-catenin in the neointima in apoE(-/-)/MMP8(+/+) mice.<p></p> CONCLUSIONS: MMP8 enhances VSMC proliferation via an ADAM10, N-cadherin, and β-catenin-mediated pathway and plays an important role in neointima formation.<p></p>

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Maffia, Professor Pasquale and Grassia, Dr Gianluca
• Authors: Xiao, Q., Zhang, F., Grassia, G., Hu, Y., Zhang, Z., Xing, Q., Yin, X., Maddaluno, M., Drung, B., Schmidt, B., Maffia, P., Ialenti, A., Mayr, M., Xu, Q., and Ye, S.
• Subjects: Q Science > QR Microbiology > QR180 Immunology; R Medicine > RM Therapeutics. Pharmacology
• College/School: College of Medical Veterinary and Life Sciences > School of Infection & Immunity
• Journal Name: Arteriosclerosis, Thrombosis, and Vascular Biology
• Publisher: American Heart Association
• ISSN: 1079-5642
• ISSN (Online): 1524-4636