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TRPV4 deletion protects heart from myocardial infarction-induced adverse remodeling via modulation of cardiac fibroblast differentiation

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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.

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Acknowledgements

This work was supported by National Institutes of Health (NIH) (R01HL119705, R01HL148585 and R15CA202847; CKT and R01AI144115; SP). We thank Ashot Minsayan for the technical assistance with MI and echocardiography.

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Correspondence to Charles K. Thodeti.

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CKT filed a patent application based on some of the findings in the MS. Rest of the authors declare no conflict of interest.

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Adapala, R.K., Kanugula, A.K., Paruchuri, S. et al. TRPV4 deletion protects heart from myocardial infarction-induced adverse remodeling via modulation of cardiac fibroblast differentiation. Basic Res Cardiol 115, 14 (2020) doi:10.1007/s00395-020-0775-5

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Keywords

  • Cardiac fibroblast
  • Cardiac fibrosis
  • Mechanotransduction
  • Myocardial infarction
  • Rho/Rho kinase
  • TGF-β1
  • TRPV4