Syndecan-4 signaling via NFAT regulates extracellular matrix production and cardiac myofibroblast differentiation in response to mechanical stress
Herum, Kate M. ; Lunde, Ida G. ; Skrbic, Biljana ; Florholmen, Geir ; Behmen, Dina ; Sjaastad, Ivar ; Carlson, Cathrine R. ; Gomez, Maria LU
and Christensen, Geir
(2013)
In Journal of Molecular and Cellular Cardiology
54.
p.73-81
- 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 alpha-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 land III, fibronectin, SMA... (More)
- 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 alpha-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 land 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'. (c) 2012 Elsevier Ltd. All rights reserved. (Less)
Please use this url to cite or link to this publication:
https://lup.lub.lu.se/record/3590888
- author
- Herum, Kate M.
; Lunde, Ida G.
; Skrbic, Biljana
; Florholmen, Geir
; Behmen, Dina
; Sjaastad, Ivar
; Carlson, Cathrine R.
; Gomez, Maria
LU
and Christensen, Geir
- organization
- publishing date
- 2013
- type
- Contribution to journal
- publication status
- published
- subject
- keywords
- Mechanical stress, Cardiac fibroblast, Extracellular matrix, Myofibroblast, Syndecan-4, NFAT
- in
- Journal of Molecular and Cellular Cardiology
- volume
- 54
- pages
- 73 - 81
- publisher
- Elsevier
- external identifiers
-
- wos:000314320500009
- scopus:84871836123
- ISSN
- 1095-8584
- DOI
- 10.1016/j.yjmcc.2012.11.006
- language
- English
- LU publication?
- yes
- id
- 66b10e87-8e50-4a3c-9944-0a2804d4c903 (old id 3590888)
- alternative location
- http://www.ncbi.nlm.nih.gov/pubmed/23178899
- date added to LUP
- 2016-04-01 13:55:25
- date last changed
- 2022-04-14 03:54:57
@article{66b10e87-8e50-4a3c-9944-0a2804d4c903,
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 alpha-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 land 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'. (c) 2012 Elsevier Ltd. All rights reserved.}},
author = {{Herum, Kate M. and Lunde, Ida G. and Skrbic, Biljana and Florholmen, Geir and Behmen, Dina and Sjaastad, Ivar and Carlson, Cathrine R. and Gomez, Maria and Christensen, Geir}},
issn = {{1095-8584}},
keywords = {{Mechanical stress; Cardiac fibroblast; Extracellular matrix; Myofibroblast; Syndecan-4; NFAT}},
language = {{eng}},
pages = {{73--81}},
publisher = {{Elsevier}},
series = {{Journal of Molecular and Cellular Cardiology}},
title = {{Syndecan-4 signaling via NFAT regulates extracellular matrix production and cardiac myofibroblast differentiation in response to mechanical stress}},
url = {{https://lup.lub.lu.se/search/files/3670503/3737711.pdf}},
doi = {{10.1016/j.yjmcc.2012.11.006}},
volume = {{54}},
year = {{2013}},
}