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2015 ; 10
(10
): e0137519
Nephropedia Template TP
Jatho A
; Hartmann S
; Kittana N
; Mügge F
; Wuertz CM
; Tiburcy M
; Zimmermann WH
; Katschinski DM
; Lutz S
PLoS One
2015[]; 10
(10
): e0137519
PMID26448568
show ga
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 ?-sm-actin, but increased
certain fibrosis-associated factors like TGF-? 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.