title: Tenascin-C may accelerate cardiac fibrosis by activating macrophages via the integrin αVβ3/nuclear factor-κB/interleukin-6 axis.
abstract: Tenascin-C (TN-C) is an extracellular matrix protein not detected in normal adult heart, but expressed in several heart diseases closely associated with inflammation. Accumulating data suggest that TN-C may play a significant role in progression of ventricular remodeling. In this study, we aimed to elucidate the role of TN-C in hypertensive cardiac fibrosis and underlying molecular mechanisms. Angiotensin II was administered to wild-type and TN-C knockout mice for 4 weeks. In wild-type mice, the treatment induced increase of collagen fibers and accumulation of macrophages in perivascular areas associated with deposition of TN-C and upregulated the expression levels of interleukin-6 and monocyte chemoattractant protein-1 as compared with wild-type/control mice. These changes were significantly reduced in TN-C knockout/angiotensin II mice. In vitro, TN-C accelerated macrophage migration and induced accumulation of integrin αVβ3 in focal adhesions, with phosphorylation of focal adhesion kinase (FAK) and Src. TN-C treatment also induced nuclear translocation of phospho-NF-κB and upregulated interleukin-6 expression of macrophages in an NF-κB-dependent manner; this being suppressed by inhibitors for integrin αVβ3 and Src. Furthermore, interleukin-6 upregulated expression of collagen I by cardiac fibroblasts. TN-C may enhance inflammatory responses by accelerating macrophage migration and synthesis of proinflammatory/profibrotic cytokines via integrin αVβ3/FAK-Src/NF-κB, resulting in increased fibrosis.
authors.affiliation: From the Department of Pathology and Matrix Biology (N.S., R.H., M.H., Y.S., T.N., M.H., T.Y., K.I.-Y.), and Department of Pathologic Oncology (K.K.), Mie University Graduate School of Medicine, Tsu, Mie, Japan; Mie University Research Center for Matrix Biology, Tsu, Mie, Japan (N.S., R.H., T.Y., K.I.-Y.); and Department of Cardiology, National Center of Global Health and Medicine, Toyama, Shinjuku-ku, Tokyo, Japan (M.H.). nshimojo@doc.medic.mie-u.ac.jp.
authors.forename: Naoshi
authors.initials: N
authors.lastname: Shimojo
authors.affiliation: From the Department of Pathology and Matrix Biology (N.S., R.H., M.H., Y.S., T.N., M.H., T.Y., K.I.-Y.), and Department of Pathologic Oncology (K.K.), Mie University Graduate School of Medicine, Tsu, Mie, Japan; Mie University Research Center for Matrix Biology, Tsu, Mie, Japan (N.S., R.H., T.Y., K.I.-Y.); and Department of Cardiology, National Center of Global Health and Medicine, Toyama, Shinjuku-ku, Tokyo, Japan (M.H.).
authors.forename: Ryotaro
authors.initials: R
authors.lastname: Hashizume
authors.affiliation: From the Department of Pathology and Matrix Biology (N.S., R.H., M.H., Y.S., T.N., M.H., T.Y., K.I.-Y.), and Department of Pathologic Oncology (K.K.), Mie University Graduate School of Medicine, Tsu, Mie, Japan; Mie University Research Center for Matrix Biology, Tsu, Mie, Japan (N.S., R.H., T.Y., K.I.-Y.); and Department of Cardiology, National Center of Global Health and Medicine, Toyama, Shinjuku-ku, Tokyo, Japan (M.H.).
authors.forename: Kazuki
authors.initials: K
authors.lastname: Kanayama
authors.affiliation: From the Department of Pathology and Matrix Biology (N.S., R.H., M.H., Y.S., T.N., M.H., T.Y., K.I.-Y.), and Department of Pathologic Oncology (K.K.), Mie University Graduate School of Medicine, Tsu, Mie, Japan; Mie University Research Center for Matrix Biology, Tsu, Mie, Japan (N.S., R.H., T.Y., K.I.-Y.); and Department of Cardiology, National Center of Global Health and Medicine, Toyama, Shinjuku-ku, Tokyo, Japan (M.H.).
authors.forename: Mari
authors.initials: M
authors.lastname: Hara
authors.affiliation: From the Department of Pathology and Matrix Biology (N.S., R.H., M.H., Y.S., T.N., M.H., T.Y., K.I.-Y.), and Department of Pathologic Oncology (K.K.), Mie University Graduate School of Medicine, Tsu, Mie, Japan; Mie University Research Center for Matrix Biology, Tsu, Mie, Japan (N.S., R.H., T.Y., K.I.-Y.); and Department of Cardiology, National Center of Global Health and Medicine, Toyama, Shinjuku-ku, Tokyo, Japan (M.H.).
authors.forename: Yuka
authors.initials: Y
authors.lastname: Suzuki
authors.affiliation: From the Department of Pathology and Matrix Biology (N.S., R.H., M.H., Y.S., T.N., M.H., T.Y., K.I.-Y.), and Department of Pathologic Oncology (K.K.), Mie University Graduate School of Medicine, Tsu, Mie, Japan; Mie University Research Center for Matrix Biology, Tsu, Mie, Japan (N.S., R.H., T.Y., K.I.-Y.); and Department of Cardiology, National Center of Global Health and Medicine, Toyama, Shinjuku-ku, Tokyo, Japan (M.H.).
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Nishioka
authors.affiliation: From the Department of Pathology and Matrix Biology (N.S., R.H., M.H., Y.S., T.N., M.H., T.Y., K.I.-Y.), and Department of Pathologic Oncology (K.K.), Mie University Graduate School of Medicine, Tsu, Mie, Japan; Mie University Research Center for Matrix Biology, Tsu, Mie, Japan (N.S., R.H., T.Y., K.I.-Y.); and Department of Cardiology, National Center of Global Health and Medicine, Toyama, Shinjuku-ku, Tokyo, Japan (M.H.).
authors.forename: Michiaki
authors.initials: M
authors.lastname: Hiroe
authors.affiliation: From the Department of Pathology and Matrix Biology (N.S., R.H., M.H., Y.S., T.N., M.H., T.Y., K.I.-Y.), and Department of Pathologic Oncology (K.K.), Mie University Graduate School of Medicine, Tsu, Mie, Japan; Mie University Research Center for Matrix Biology, Tsu, Mie, Japan (N.S., R.H., T.Y., K.I.-Y.); and Department of Cardiology, National Center of Global Health and Medicine, Toyama, Shinjuku-ku, Tokyo, Japan (M.H.).
authors.forename: Toshimichi
authors.initials: T
authors.lastname: Yoshida
authors.affiliation: From the Department of Pathology and Matrix Biology (N.S., R.H., M.H., Y.S., T.N., M.H., T.Y., K.I.-Y.), and Department of Pathologic Oncology (K.K.), Mie University Graduate School of Medicine, Tsu, Mie, Japan; Mie University Research Center for Matrix Biology, Tsu, Mie, Japan (N.S., R.H., T.Y., K.I.-Y.); and Department of Cardiology, National Center of Global Health and Medicine, Toyama, Shinjuku-ku, Tokyo, Japan (M.H.).
authors.forename: Kyoko
authors.initials: K
authors.lastname: Imanaka-Yoshida
mesh_terms: D000818:Animals; D015153:Blotting, Western; D054442:Cell Migration Assays, Macrophage; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology; D005355:Fibrosis / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D005455:Fluorescent Antibody Technique; D005786:Gene Expression Regulation; D006331:Heart Diseases / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D007150:Immunohistochemistry; D039302:Integrin alphaVbeta3 / Q000096:biosynthesis / Q000235:genetics*; D015850:Interleukin-6 / Q000096:biosynthesis / Q000235:genetics*; D008262:Macrophage Activation / Q000235:genetics*; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins; D012333:RNA, Messenger / Q000235:genetics*; D060888:Real-Time Polymerase Chain Reaction; D019063:Tenascin / Q000096:biosynthesis / Q000235:genetics*
chemical_list: D039302:Integrin alphaVbeta3; D015850:Interleukin-6; D009419:Nerve Tissue Proteins; D012333:RNA, Messenger; D019063:Tenascin; C477504:tenascin-N protein, mouse
keywords: angiotensin II; cardiac fibrosis; hypertension; remodeling; tenascin-C