title: RhoA Ambivalently Controls Prominent Myofibroblast Characteritics by Involving Distinct Signaling Routes.
abstract: BACKGROUND
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Institute of Pharmacology, University Medical Center Göttingen, Georg-August-University, Germany; Department of Cardiovascular Physiology, University Medical Center Göttingen, Georg-August-University, Germany; DZHK (German Center for Cardiovascular Research), partner site Göttingen, Germany.
authors.forename: Aline
authors.initials: A
authors.lastname: Jatho
authors.affiliation: Institute of Pharmacology, University Medical Center Göttingen, Georg-August-University, Germany; DZHK (German Center for Cardiovascular Research), partner site Göttingen, Germany; Division of Cell and Molecular Biophysics, King´s College London, London, United Kingdom.
authors.forename: Svenja
authors.initials: S
authors.lastname: Hartmann
authors.affiliation: Institute of Pharmacology, University Medical Center Göttingen, Georg-August-University, Germany.
authors.forename: Naim
authors.initials: N
authors.lastname: Kittana
authors.affiliation: Institute of Pharmacology, University Medical Center Göttingen, Georg-August-University, Germany.
authors.forename: Felicitas
authors.initials: F
authors.lastname: Mügge
authors.affiliation: Institute of Pharmacology, University Medical Center Göttingen, Georg-August-University, Germany; DZHK (German Center for Cardiovascular Research), partner site Göttingen, Germany.
authors.forename: Christina M
authors.initials: CM
authors.lastname: Wuertz
authors.affiliation: Institute of Pharmacology, University Medical Center Göttingen, Georg-August-University, Germany; DZHK (German Center for Cardiovascular Research), partner site Göttingen, Germany.
authors.forename: Malte
authors.initials: M
authors.lastname: Tiburcy
authors.affiliation: Institute of Pharmacology, University Medical Center Göttingen, Georg-August-University, Germany; DZHK (German Center for Cardiovascular Research), partner site Göttingen, Germany.
authors.forename: Wolfram-Hubertus
authors.initials: WH
authors.lastname: Zimmermann
authors.affiliation: Department of Cardiovascular Physiology, University Medical Center Göttingen, Georg-August-University, Germany; DZHK (German Center for Cardiovascular Research), partner site Göttingen, Germany.
authors.forename: Dörthe M
authors.initials: DM
authors.lastname: Katschinski
authors.affiliation: Institute of Pharmacology, University Medical Center Göttingen, Georg-August-University, Germany; DZHK (German Center for Cardiovascular Research), partner site Göttingen, Germany.
authors.forename: Susanne
authors.initials: S
authors.lastname: Lutz
mesh_terms: D000818:Animals; D002465:Cell Movement / Q000235:genetics / Q000502:physiology; D002470:Cell Survival / Q000235:genetics / Q000502:physiology; D002478:Cells, Cultured / Q000502:physiology; D058628:Myofibroblasts / Q000378:metabolism*; D016133:Polymerase Chain Reaction; D051381:Rats; D015398:Signal Transduction / Q000502:physiology; D020742:rhoA GTP-Binding Protein / Q000235:genetics / Q000378:metabolism*
chemical_list: D020742:rhoA GTP-Binding Protein