Abstract 19870: TRPV4 Channel Deletion Improves Cardiac Remodeling Following Pressure-Overload via Modulation of Mechanosensitive Rho/MRTF-A Pathway
Cardiac fibroblast (CF) differentiation is a critical event in the remodeling of the myocardium following cardiac injury. We have recently shown that mechanosensitive ion channel Transient Receptor Potential Vanilloid 4 (TRPV4) plays a key role in regulating CF differentiation by integrating soluble and mechanical signaling in rat cardiac fibroblasts. Here, we investigated the physiological significance of TRPV4 and the molecular mechanisms involved following pressure-overload. We induced pressure-overload using Trans Aortic Constriction (TAC) in wild type (WT) and TRPV4 knockout (KO) mice and monitored cardiac function for 28 days. We found that TRPV4KO mice exhibited decreased myocardial cross sectional area and left ventricular mass when compared with WT. Next, we analyzed cardiac function using 2D echocardiography, which revealed that TRPV4KO mice had preserved cardiac function (ejection fraction and fractional shortening) 28 days post-TAC. Histological analysis demonstrated that TRPV4KO mice displayed reduced cardiac fibrosis, as evidenced by picro-sirius red staining. To find out the molecular mechanism, we stimulated CFs isolated from WT and TRPV4KO mice with TGF-β1 and found that TGF-β1-induced differentiation was attenuated in TRPV4KO mCF. Further, both TGF-β1 and a specific activator of TRPV4, GSK1016790A, significantly enhanced α-SMA and Col1α1 promoter activities. Mechanistically, we found that both TGF-β1 and GSK induced TRPV4-dependent activation of the Rho/Rho Kinase pathway as well as a mechanosensitive transcription factor MRTF-A. Importantly, inhibition of Rho kinase or MRTF-A significantly inhibited TRPV4-mediated CF differentiation. Taken together, these findings suggest that the deletion of TRPV4 channels preserve cardiac function following TAC by modulating Rho/MRTF-A-induced cardiac fibrosis.
Author Disclosures: R. Adapala: None. V.A. Ohanyan: None. H.C. Cappelli: None. A.K. Kanugula: None. J. Luli: None. R.J. Thoppil: None. S. Paruchuri: None. G.J. Meszaros: None. C.K. Thodeti: None.
- © 2016 by American Heart Association, Inc.