Syndecan-4 signaling via NFAT regulates extracellular matrix production and cardiac myofibroblast differentiation in response to mechanical stress

J Mol Cell Cardiol. 2013 Jan;54:73-81. doi: 10.1016/j.yjmcc.2012.11.006. Epub 2012 Nov 22.

Abstract

Pressure overload activates cardiac fibroblasts leading to excessive production of extracellular matrix which may contribute to compromised heart function. The activated fibroblast acquires smooth muscle-like features such as expression of smooth muscle α-actin (SMA) and SM22 and is therefore referred to as myofibroblast. The molecular mechanisms underlying mechanical stress-induced myofibroblast differentiation are poorly defined. The objective of this study was to examine the potential roles of the transmembrane proteoglycan syndecan-4 and the calcineurin-dependent transcription factor nuclear factor of activated T-cells (NFAT) in myofibroblast differentiation. Aortic banding resulted in elevated collagen I and III, fibronectin, SMA and SM22 mRNA in the left ventricles of wild-type mice, whereas this response was markedly reduced in syndecan-4(-/-) mice. Myofibroblast differentiation in vitro was associated with increased SMA, collagen I and III expression and NFAT-luciferase activity, all of which were reduced in fibroblasts from syndecan-4(-/-) mice or after treatment with calcineurin/NFAT blockers. Following cyclic stretch, NFATc4 was activated in cardiac fibroblasts in a syndecan-4- and calcineurin-dependent manner. Syndecan-4 and calcineurin co-localized and mechanical stress resulted in dephosphorylation of serine179 of syndecan-4, an intracellular residue critical for calcineurin interaction. Over-expression of NFATc4 up-regulated collagen III, MRTF-A (a transcriptional regulator of SMA) and the NFAT-target regulator of calcineurin 1.4 (RCAN1.4). Our data demonstrate that syndecan-4 is important for the differentiation of cardiac fibroblasts into myofibroblasts in the pressure-overloaded heart and that the calcineurin/NFAT pathway is engaged upon mechanical stress in a syndecan-4-dependent manner, playing an active role in myofibroblast differentiation and extracellular matrix production. This article is part of a Special Issue entitled 'Possible Editorial'.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Actin Cytoskeleton / metabolism
  • Animals
  • Calcineurin / metabolism
  • Cell Differentiation*
  • Cells, Cultured
  • Collagen Type I / genetics
  • Collagen Type I / metabolism
  • Collagen Type III / genetics
  • Collagen Type III / metabolism
  • Extracellular Matrix Proteins / genetics
  • Extracellular Matrix Proteins / metabolism
  • Gene Expression
  • Gene Expression Regulation
  • Male
  • Mechanotransduction, Cellular
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Myocardium / pathology
  • Myofibroblasts / physiology*
  • NFATC Transcription Factors / metabolism*
  • Phosphorylation
  • Protein Processing, Post-Translational
  • Protein Transport
  • Stress, Physiological
  • Syndecan-4 / metabolism*
  • Trans-Activators / genetics
  • Trans-Activators / metabolism
  • Ventricular Pressure

Substances

  • Collagen Type I
  • Collagen Type III
  • Extracellular Matrix Proteins
  • Mrtfa protein, mouse
  • NFATC Transcription Factors
  • Nfatc4 protein, mouse
  • Sdc4 protein, mouse
  • Syndecan-4
  • Trans-Activators
  • Calcineurin