Article (Scientific journals)
Mechanical strain induces a pro-fibrotic phenotype in human mitral valvular interstitial cells through RhoC/ROCK/MRTF-A and Erk1/2 signaling pathways
Blomme, Benoit; Deroanne, Christophe; Hulin, Alexia et al.
2019In Journal of Molecular and Cellular Cardiology, 135, p. 149-159
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Keywords :
CTGF/CCN2; Heart valve disease; Mechanical strain; MMV; MRTF-A; RhoGTPases
Abstract :
[en] The mitral valve is a complex multilayered structure populated by fibroblast-like cells, valvular interstitial cells (VIC) which are embedded in an extracellular matrix (ECM) scaffold and are submitted to the mechanical deformations affecting valve at each heartbeat, for an average of 40 million times per year. Myxomatous mitral valve (MMV) is the most frequent heart valve disease characterized by disruption of several valvular structures due to alterations of their ECM preventing the complete closure of the valve resulting in symptoms of prolapse and regurgitation. VIC and their ECM exhibit reciprocal dynamic processes between the mechanical signals issued from the ECM and the modulation of VIC phenotype responsible for ECM homeostasis of the valve. Abnormal perception and responsiveness of VIC to mechanical stress may induce an inappropriate adaptative remodeling of the valve progressively leading to MMV. To investigate the response of human VIC to mechanical strain and identify the molecular mechanisms of mechano-transduction in these cells, a cyclic equibiaxial elongation of 14% at the cardiac frequency of 1.16 Hz was applied to VIC by using a Flexercell-4000 T™ apparatus for increasing time (from 1 h to 8 h). We showed that cyclic stretch induces an early (1 h) and transient over-expression of TGFβ2 and αSMA. CTGF, a profibrotic growth factor promoting the synthesis of ECM components, was strongly induced after 1 and 2 h of stretching and still upregulated at 8 h. The mechanical stress-induced CTGF up-regulation was dependent on RhoC, but not RhoA, as demonstrated by siRNA-mediated silencing approaches, and further supported by evidencing RhoC activation upon cell stretching and suppression of cell response by pharmacological inhibition of the effector ROCK1/2. It was also dependent on the MEK/Erk1/2 pathway which was activated by mechanical stress independently of RhoC and ROCK. Finally, mechanical stretching induced the nuclear translocation of myocardin related transcription factor-A (MRTF-A) which forms a transcriptional complex with SRF to promote the expression of target genes, notably CTGF. Treatment of stretched cultures with inhibitors of the identified pathways (ROCK1/2, MEK/Erk1/2, MRTF-A translocation) blocked CTGF overexpression and abrogated the increased MRTF-A nuclear translocation. CTGF is up-regulated in many pathological processes involving mechanically challenged organs, promotes ECM accumulation and is considered as a hallmark of fibrotic diseases. Pharmacological targeting of MRTF-A by newly developed inhibitors may represent a relevant therapy for MMV. © 2019
Research center :
Giga-Cancer - ULiège
Disciplines :
Biochemistry, biophysics & molecular biology
Cardiovascular & respiratory systems
Author, co-author :
Blomme, Benoit  ;  Université de Liège - ULiège > Doct. sc. bioméd. & pharma. (paysage)
Deroanne, Christophe  ;  Université de Liège - ULiège > Cancer-Connective Tissue Biology
Hulin, Alexia ;  Université de Liège - ULiège > Cardiovascular Sciences-Cardiology
Lambert, Charles ;  Université de Liège - ULiège > Cancer-Connective Tissue Biology
Defraigne, Jean-Olivier ;  Université de Liège - ULiège > Département des sciences cliniques > Chirurgie cardio-vasculaire et thoracique
Nusgens, Betty ;  Laboratory of Connective Tissues Biology, GIGA-Research, University of Liège, Tour de Pathologie, B23, Sart-Tilman, 4000, Belgium
Radermecker, Maurice ;  Université de Liège - ULiège > Relations académiques et scientifiques (Médecine)
Colige, Alain ;  Université de Liège - ULiège > Cancer-Connective Tissue Biology
 These authors have contributed equally to this work.
Language :
Title :
Mechanical strain induces a pro-fibrotic phenotype in human mitral valvular interstitial cells through RhoC/ROCK/MRTF-A and Erk1/2 signaling pathways
Publication date :
20 August 2019
Journal title :
Journal of Molecular and Cellular Cardiology
Publisher :
Volume :
Pages :
Peer reviewed :
Peer Reviewed verified by ORBi
Name of the research project :
Funders :
F.R.S.-FNRS - Fonds de la Recherche Scientifique [BE]
BELSPO - Service Public Fédéral de Programmation Politique scientifique [BE]
Funding text :
J. Grommersch Award
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since 19 February 2020


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