title: Syndecan-4 is essential for development of concentric myocardial hypertrophy via stretch-induced activation of the calcineurin-NFAT pathway.
abstract: Sustained pressure overload leads to compensatory myocardial hypertrophy and subsequent heart failure, a leading cause of morbidity and mortality. Further unraveling of the cellular processes involved is essential for development of new treatment strategies. We have investigated the hypothesis that the transmembrane Z-disc proteoglycan syndecan-4, a co-receptor for integrins, connecting extracellular matrix proteins to the cytoskeleton, is an important signal transducer in cardiomyocytes during development of concentric myocardial hypertrophy following pressure overload. Echocardiographic, histochemical and cardiomyocyte size measurements showed that syndecan-4(-/-) mice did not develop concentric myocardial hypertrophy as found in wild-type mice, but rather left ventricular dilatation and dysfunction following pressure overload. Protein and gene expression analyses revealed diminished activation of the central, pro-hypertrophic calcineurin-nuclear factor of activated T-cell (NFAT) signaling pathway. Cardiomyocytes from syndecan-4(-/-)-NFAT-luciferase reporter mice subjected to cyclic mechanical stretch, a hypertrophic stimulus, showed minimal activation of NFAT (1.6-fold) compared to 5.8-fold increase in NFAT-luciferase control cardiomyocytes. Accordingly, overexpression of syndecan-4 or introducing a cell-permeable membrane-targeted syndecan-4 polypeptide (gain of function) activated NFATc4 in vitro. Pull-down experiments demonstrated a direct intracellular syndecan-4-calcineurin interaction. This interaction and activation of NFAT were increased by dephosphorylation of serine 179 (pS179) in syndecan-4. During pressure overload, phosphorylation of syndecan-4 was decreased, and association between syndecan-4, calcineurin and its co-activator calmodulin increased. Moreover, calcineurin dephosphorylated pS179, indicating that calcineurin regulates its own binding and activation. Finally, patients with hypertrophic myocardium due to aortic stenosis had increased syndecan-4 levels with decreased pS179 which was associated with increased NFAT activation. In conclusion, our data show that syndecan-4 is essential for compensatory hypertrophy in the pressure overloaded heart. Specifically, syndecan-4 regulates stretch-induced activation of the calcineurin-NFAT pathway in cardiomyocytes. Thus, our data suggest that manipulation of syndecan-4 may provide an option for therapeutic modulation of calcineurin-NFAT signaling.
authors.affiliation: Institute for Experimental Medical Research, Oslo University Hospital Ullevål, Oslo, Norway. a.v.finsen@medisin.uio.no
authors.forename: Alexandra V
authors.initials: AV
authors.lastname: Finsen
authors.forename: Ida G
authors.initials: IG
authors.lastname: Lunde
authors.forename: Ivar
authors.initials: I
authors.lastname: Sjaastad
authors.forename: Even K
authors.initials: EK
authors.lastname: Østli
authors.forename: Marianne
authors.initials: M
authors.lastname: Lyngra
authors.forename: Hilde O
authors.initials: HO
authors.lastname: Jarstadmarken
authors.forename: Almira
authors.initials: A
authors.lastname: Hasic
authors.forename: Ståle
authors.initials: S
authors.lastname: Nygård
authors.forename: Sarah A
authors.initials: SA
authors.lastname: Wilcox-Adelman
authors.forename: Paul F
authors.initials: PF
authors.lastname: Goetinck
authors.forename: Torstein
authors.initials: T
authors.lastname: Lyberg
authors.forename: Biljana
authors.initials: B
authors.lastname: Skrbic
authors.forename: Geir
authors.initials: G
authors.lastname: Florholmen
authors.forename: Theis
authors.initials: T
authors.lastname: Tønnessen
authors.forename: William E
authors.initials: WE
authors.lastname: Louch
authors.forename: Srdjan
authors.initials: S
authors.lastname: Djurovic
authors.forename: Cathrine R
authors.initials: CR
authors.lastname: Carlson
authors.forename: Geir
authors.initials: G
authors.lastname: Christensen
mesh_terms: D000818:Animals; D001024:Aortic Valve Stenosis / Q000473:pathology; D019703:Calcineurin / Q000378:metabolism*; D002147:Calmodulin / Q000378:metabolism; D002462:Cell Membrane / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D006984:Hypertrophy / Q000378:metabolism* / Q000473:pathology; D017379:Hypertrophy, Left Ventricular / Q000473:pathology; D008156:Luciferases / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D008954:Models, Biological; D009206:Myocardium / Q000473:pathology*; D050778:NFATC Transcription Factors / Q000378:metabolism*; D010766:Phosphorylation; D015398:Signal Transduction; D053671:Syndecan-4 / Q000235:genetics / Q000502:physiology*
chemical_list: D002147:Calmodulin; D050778:NFATC Transcription Factors; D053671:Syndecan-4; D008156:Luciferases; D019703:Calcineurin