Tenascin-C may accelerate cardiac fibrosis by activating macrophages via the integrin αVβ3/nuclear factor-κB/interleukin-6 axis

Hypertension. 2015 Oct;66(4):757-66. doi: 10.1161/HYPERTENSIONAHA.115.06004. Epub 2015 Aug 3.

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.

Keywords: angiotensin II; cardiac fibrosis; hypertension; remodeling; tenascin-C.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blotting, Western
  • Cell Migration Assays, Macrophage
  • Cells, Cultured
  • Disease Models, Animal
  • Fibroblasts / metabolism
  • Fibroblasts / pathology
  • Fibrosis / genetics
  • Fibrosis / metabolism
  • Fibrosis / pathology
  • Fluorescent Antibody Technique
  • Gene Expression Regulation*
  • Heart Diseases / genetics*
  • Heart Diseases / metabolism
  • Heart Diseases / pathology
  • Immunohistochemistry
  • Integrin alphaVbeta3 / biosynthesis
  • Integrin alphaVbeta3 / genetics*
  • Interleukin-6 / biosynthesis
  • Interleukin-6 / genetics*
  • Macrophage Activation / genetics*
  • Mice
  • Mice, Inbred BALB C
  • Mice, Knockout
  • Nerve Tissue Proteins
  • RNA, Messenger / genetics*
  • Real-Time Polymerase Chain Reaction
  • Tenascin / biosynthesis
  • Tenascin / genetics*

Substances

  • Integrin alphaVbeta3
  • Interleukin-6
  • Nerve Tissue Proteins
  • RNA, Messenger
  • Tenascin
  • tenascin-N protein, mouse