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TRPV4 deletion protects heart from myocardial infarction-induced adverse remodeling via modulation of cardiac fibroblast differentiation.
- Source :
-
Basic research in cardiology [Basic Res Cardiol] 2020 Jan 10; Vol. 115 (2), pp. 14. Date of Electronic Publication: 2020 Jan 10. - Publication Year :
- 2020
-
Abstract
- Cardiac fibrosis caused by adverse cardiac remodeling following myocardial infarction can eventually lead to heart failure. Although the role of soluble factors such as TGF-β is well studied in cardiac fibrosis following myocardial injury, the physiological role of mechanotransduction is not fully understood. Here, we investigated the molecular mechanism and functional role of TRPV4 mechanotransduction in cardiac fibrosis. TRPV4KO mice, 8 weeks following myocardial infarction (MI), exhibited preserved cardiac function compared to WT mice. Histological analysis demonstrated reduced cardiac fibrosis in TRPV4KO mice. We found that WT CF exhibited hypotonicity-induced calcium influx and extracellular matrix (ECM)-stiffness-dependent differentiation in response to TGF-β1. In contrast, TRPV4KO CF did not display hypotonicity-induced calcium influx and failed to differentiate on high-stiffness ECM gels even in the presence of saturating amounts of TGF-β1. Mechanistically, TRPV4 mediated cardiac fibrotic gene promoter activity and fibroblast differentiation through the activation of the Rho/Rho kinase pathway and the mechanosensitive transcription factor MRTF-A. Our findings suggest that genetic deletion of TRPV4 channels protects heart from adverse cardiac remodeling following MI by modulating Rho/MRTF-A pathway-mediated cardiac fibroblast differentiation and cardiac fibrosis.
- Subjects :
- Animals
Calcium Signaling
Cells, Cultured
Disease Models, Animal
Extracellular Matrix metabolism
Extracellular Matrix pathology
Fibroblasts pathology
Fibrosis
Mechanotransduction, Cellular
Mice, Inbred C57BL
Mice, Knockout
Myocardial Infarction metabolism
Myocardial Infarction pathology
Myocardial Infarction physiopathology
Myocardium pathology
TRPV Cation Channels genetics
Trans-Activators metabolism
rho GTP-Binding Proteins metabolism
rho-Associated Kinases metabolism
Cell Differentiation
Fibroblasts metabolism
Gene Deletion
Myocardial Infarction prevention & control
Myocardium metabolism
TRPV Cation Channels deficiency
Ventricular Remodeling
Subjects
Details
- Language :
- English
- ISSN :
- 1435-1803
- Volume :
- 115
- Issue :
- 2
- Database :
- MEDLINE
- Journal :
- Basic research in cardiology
- Publication Type :
- Academic Journal
- Accession number :
- 31925567
- Full Text :
- https://doi.org/10.1007/s00395-020-0775-5