RhoA Ambivalently Controls Prominent Myofibroblast Characteritics by Involving Distinct Signaling Routes

INTRODUCTION: RhoA has been shown to be beneficial in cardiac disease models when overexpressed in cardiomyocytes, whereas its role in cardiac fibroblasts (CF) is still poorly understood. During cardiac remodeling CF undergo a transition towards a myofibroblast phenotype thereby showing an increased...

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Autores principales: Jatho, Aline, Hartmann, Svenja, Kittana, Naim, Mügge, Felicitas, Wuertz, Christina M., Tiburcy, Malte, Zimmermann, Wolfram-Hubertus, Katschinski, Dörthe M., Lutz, Susanne
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4598021/
https://www.ncbi.nlm.nih.gov/pubmed/26448568
http://dx.doi.org/10.1371/journal.pone.0137519
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author Jatho, Aline
Hartmann, Svenja
Kittana, Naim
Mügge, Felicitas
Wuertz, Christina M.
Tiburcy, Malte
Zimmermann, Wolfram-Hubertus
Katschinski, Dörthe M.
Lutz, Susanne
author_facet Jatho, Aline
Hartmann, Svenja
Kittana, Naim
Mügge, Felicitas
Wuertz, Christina M.
Tiburcy, Malte
Zimmermann, Wolfram-Hubertus
Katschinski, Dörthe M.
Lutz, Susanne
author_sort Jatho, Aline
collection PubMed
description INTRODUCTION: RhoA has been shown to be beneficial in cardiac disease models when overexpressed in cardiomyocytes, whereas its role in cardiac fibroblasts (CF) is still poorly understood. During cardiac remodeling CF undergo a transition towards a myofibroblast phenotype thereby showing an increased proliferation and migration rate. Both processes involve the remodeling of the cytoskeleton. Since RhoA is known to be a major regulator of the cytoskeleton, we analyzed its role in CF and its effect on myofibroblast characteristics in 2 D and 3D models. RESULTS: Downregulation of RhoA was shown to strongly affect the actin cytoskeleton. It decreased the myofibroblast marker α-sm-actin, but increased certain fibrosis-associated factors like TGF-β and collagens. Also, the detailed analysis of CTGF expression demonstrated that the outcome of RhoA signaling strongly depends on the involved stimulus. Furthermore, we show that proliferation of myofibroblasts rely on RhoA and tubulin acetylation. In assays accessing three different types of migration, we demonstrate that RhoA/ROCK/Dia1 are important for 2D migration and the repression of RhoA and Dia1 signaling accelerates 3D migration. Finally, we show that a downregulation of RhoA in CF impacts the viscoelastic and contractile properties of engineered tissues. CONCLUSION: RhoA positively and negatively influences myofibroblast characteristics by differential signaling cascades and depending on environmental conditions. These include gene expression, migration and proliferation. Reduction of RhoA leads to an increased viscoelasticity and a decrease in contractile force in engineered cardiac tissue.
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spelling pubmed-45980212015-10-20 RhoA Ambivalently Controls Prominent Myofibroblast Characteritics by Involving Distinct Signaling Routes Jatho, Aline Hartmann, Svenja Kittana, Naim Mügge, Felicitas Wuertz, Christina M. Tiburcy, Malte Zimmermann, Wolfram-Hubertus Katschinski, Dörthe M. Lutz, Susanne PLoS One Research Article INTRODUCTION: RhoA has been shown to be beneficial in cardiac disease models when overexpressed in cardiomyocytes, whereas its role in cardiac fibroblasts (CF) is still poorly understood. During cardiac remodeling CF undergo a transition towards a myofibroblast phenotype thereby showing an increased proliferation and migration rate. Both processes involve the remodeling of the cytoskeleton. Since RhoA is known to be a major regulator of the cytoskeleton, we analyzed its role in CF and its effect on myofibroblast characteristics in 2 D and 3D models. RESULTS: Downregulation of RhoA was shown to strongly affect the actin cytoskeleton. It decreased the myofibroblast marker α-sm-actin, but increased certain fibrosis-associated factors like TGF-β and collagens. Also, the detailed analysis of CTGF expression demonstrated that the outcome of RhoA signaling strongly depends on the involved stimulus. Furthermore, we show that proliferation of myofibroblasts rely on RhoA and tubulin acetylation. In assays accessing three different types of migration, we demonstrate that RhoA/ROCK/Dia1 are important for 2D migration and the repression of RhoA and Dia1 signaling accelerates 3D migration. Finally, we show that a downregulation of RhoA in CF impacts the viscoelastic and contractile properties of engineered tissues. CONCLUSION: RhoA positively and negatively influences myofibroblast characteristics by differential signaling cascades and depending on environmental conditions. These include gene expression, migration and proliferation. Reduction of RhoA leads to an increased viscoelasticity and a decrease in contractile force in engineered cardiac tissue. Public Library of Science 2015-10-08 /pmc/articles/PMC4598021/ /pubmed/26448568 http://dx.doi.org/10.1371/journal.pone.0137519 Text en © 2015 Jatho et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Jatho, Aline
Hartmann, Svenja
Kittana, Naim
Mügge, Felicitas
Wuertz, Christina M.
Tiburcy, Malte
Zimmermann, Wolfram-Hubertus
Katschinski, Dörthe M.
Lutz, Susanne
RhoA Ambivalently Controls Prominent Myofibroblast Characteritics by Involving Distinct Signaling Routes
title RhoA Ambivalently Controls Prominent Myofibroblast Characteritics by Involving Distinct Signaling Routes
title_full RhoA Ambivalently Controls Prominent Myofibroblast Characteritics by Involving Distinct Signaling Routes
title_fullStr RhoA Ambivalently Controls Prominent Myofibroblast Characteritics by Involving Distinct Signaling Routes
title_full_unstemmed RhoA Ambivalently Controls Prominent Myofibroblast Characteritics by Involving Distinct Signaling Routes
title_short RhoA Ambivalently Controls Prominent Myofibroblast Characteritics by Involving Distinct Signaling Routes
title_sort rhoa ambivalently controls prominent myofibroblast characteritics by involving distinct signaling routes
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4598021/
https://www.ncbi.nlm.nih.gov/pubmed/26448568
http://dx.doi.org/10.1371/journal.pone.0137519
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