TRPV4 channels mediate cardiac fibroblast differentiation by integrating mechanical and soluble signals.

TRPV4 channels mediate cardiac fibroblast differentiation by integrating mechanical and soluble signals.

Adapala Ravi K; Thoppil Roslin J; Luther Daniel J; Paruchuri Sailaja; Meszaros J Gary; Chilian William M; Thodeti Charles K

Journal of molecular and cellular cardiology

2013

2013-01

The phenotypic switch underlying the differentiation of cardiac fibroblasts into hypersecretory myofibroblasts is critical for cardiac remodeling following myocardial infarction. Myofibroblasts facilitate wound repair in the myocardium by secreting and organizing extracellular matrix (ECM) during the wound healing process. However, the molecular mechanisms involved in myofibroblast differentiation are not well known. TGF-beta has been shown to promote differentiation and this, combined with the robust mechanical environment in the heart, lead us to hypothesize that the mechanotransduction and TGF-beta signaling pathways play active roles in the differentiation of cardiac fibroblasts to myofibroblasts. Here, we show that the mechanosensitve ion channel TRPV4 is required for TGF-beta1-induced differentiation of cardiac fibroblasts into myofibroblasts. We found that the TRPV4-specific antagonist AB159908 and siRNA knockdown of TRPV4 significantly inhibited TGFbeta1-induced differentiation as measured by incorporation of alpha-SMA into stress fibers. Further, we found that

*Calcium Signaling; *Cell Differentiation; *Mechanotransduction; Animals; Cellular; Extracellular Matrix/metabolism/physiology; Fibroblasts/*physiology; Gene Knockdown Techniques; Male; Monoterpenes/pharmacology; Myocardium/cytology; Myofibroblasts/metabolism; Rats; RNA; Small Interfering/genetics; Sprague-Dawley; Transforming Growth Factor beta1/physiology; TRPM Cation Channels/antagonists & inhibitors/metabolism; TRPV Cation Channels/genetics/*metabolism

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