title: Syndecan-4 signaling via NFAT regulates extracellular matrix production and cardiac myofibroblast differentiation in response to mechanical stress.
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'.
authors.affiliation: Institute for Experimental Medical Research, Oslo University Hospital and University of Oslo, Oslo, Norway. k.l.m.herum@medisin.uio.no
authors.forename: Kate M
authors.initials: KM
authors.lastname: Herum
authors.forename: Ida G
authors.initials: IG
authors.lastname: Lunde
authors.forename: Biljana
authors.initials: B
authors.lastname: Skrbic
authors.forename: Geir
authors.initials: G
authors.lastname: Florholmen
authors.forename: Dina
authors.initials: D
authors.lastname: Behmen
authors.forename: Ivar
authors.initials: I
authors.lastname: Sjaastad
authors.forename: Cathrine R
authors.initials: CR
authors.lastname: Carlson
authors.forename: Maria F
authors.initials: MF
authors.lastname: Gomez
authors.forename: Geir
authors.initials: G
authors.lastname: Christensen
mesh_terms: D008841:Actin Cytoskeleton / Q000378:metabolism; D000818:Animals; D019703:Calcineurin / Q000378:metabolism; D002454:Cell Differentiation; D002478:Cells, Cultured; D024042:Collagen Type I / Q000235:genetics / Q000378:metabolism; D024061:Collagen Type III / Q000235:genetics / Q000378:metabolism; D016326:Extracellular Matrix Proteins / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression; D005786:Gene Expression Regulation; D008297:Male; D040542:Mechanotransduction, Cellular; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009206:Myocardium / Q000473:pathology; D058628:Myofibroblasts / Q000502:physiology*; D050778:NFATC Transcription Factors / Q000378:metabolism*; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D021381:Protein Transport; D013312:Stress, Physiological; D053671:Syndecan-4 / Q000378:metabolism*; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism; D017725:Ventricular Pressure
chemical_list: D024042:Collagen Type I; D024061:Collagen Type III; D016326:Extracellular Matrix Proteins; C511173:Mrtfa protein, mouse; D050778:NFATC Transcription Factors; C467907:Nfatc4 protein, mouse; C508306:Sdc4 protein, mouse; D053671:Syndecan-4; D015534:Trans-Activators; D019703:Calcineurin