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TRPV4 deletion protects heart from myocardial infarction-induced adverse remodeling via modulation of cardiac fibroblast differentiation
- Source :
- Basic Res Cardiol
- Publication Year :
- 2020
- Publisher :
- Springer Science and Business Media LLC, 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 :
- rho GTP-Binding Proteins
0301 basic medicine
Cardiac function curve
medicine.medical_specialty
Physiology
Cardiac fibrosis
Myocardial Infarction
TRPV Cation Channels
030204 cardiovascular system & hematology
Mechanotransduction, Cellular
Article
Extracellular matrix
03 medical and health sciences
0302 clinical medicine
Physiology (medical)
Internal medicine
medicine
Animals
Calcium Signaling
Myocardial infarction
Mechanotransduction
Fibroblast
Rho-associated protein kinase
Cells, Cultured
Mice, Knockout
rho-Associated Kinases
Ventricular Remodeling
business.industry
Myocardium
Cell Differentiation
Fibroblasts
medicine.disease
Fibrosis
Extracellular Matrix
Mice, Inbred C57BL
Disease Models, Animal
030104 developmental biology
medicine.anatomical_structure
Endocrinology
Heart failure
Trans-Activators
cardiovascular system
Cardiology and Cardiovascular Medicine
business
Gene Deletion
Subjects
Details
- ISSN :
- 14351803 and 03008428
- Volume :
- 115
- Database :
- OpenAIRE
- Journal :
- Basic Research in Cardiology
- Accession number :
- edsair.doi.dedup.....838dda97c0ea7b7be5e5182660f05d7c