2026-04-18T07:07:33Zhttps://recercat.cat/oai/request

oai:recercat.cat:10230/682792025-12-20T16:55:21Zcom_2072_6col_2072_452952

TRPV4 channels promote pathological, but not physiological, cardiac remodeling through the activation of calcineurin/NFAT and TRPC6 Yáñez Bisbe, Laia, 1993- Moya, Mar Rodríguez-Sinovas, Antonio Ruiz-Meana, Marisol Inserte, Javier Tajes Orduña, Marta Batlle, Montserrat Guasch, Eduard Mas Stachurska, Aleksandra Miró, Elisabet Rivas, Nuria Ferreira González, Ignacio Garcia-Elias Heras, Anna Benito Villabriga, Begoña TRP TRPC6 TRPV4 Calcium Exercise Heart failure Mechanoreceptors Mechanotransduction Pathological remodeling Physiological remodeling TRPV4 channels, which respond to mechanical activation by permeating Ca2+ into the cell, may play a pivotal role in cardiac remodeling during cardiac overload. Our study aimed to investigate TRPV4 involvement in pathological and physiological remodeling through Ca2+-dependent signaling. TRPV4 expression was assessed in heart failure (HF) models, induced by isoproterenol infusion or transverse aortic constriction, and in exercise-induced adaptive remodeling models. The impact of genetic TRPV4 inhibition on HF was studied by echocardiography, histology, gene and protein analysis, arrhythmia inducibility, Ca2+ dynamics, calcineurin (CN) activity, and NFAT nuclear translocation. TRPV4 expression exclusively increased in HF models, strongly correlating with fibrosis. Isoproterenol-administered transgenic TRPV4-/- mice did not exhibit HF features. Cardiac fibroblasts (CFb) from TRPV4+/+ animals, compared to TRPV4-/-, displayed significant TRPV4 overexpression, elevated Ca2+ influx, and enhanced CN/NFATc3 pathway activation. TRPC6 expression paralleled that of TRPV4 in all models, with no increase in TRPV4-/- mice. In cultured CFb, the activation of TRPV4 by GSK1016790A increased TRPC6 expression, which led to enhanced CN/NFATc3 activation through synergistic action of both channels. In conclusion, TRPV4 channels contribute to pathological remodeling by promoting fibrosis and inducing TRPC6 upregulation through the activation of Ca2+-dependent CN/NFATc3 signaling. These results pose TRPV4 as a primary mediator of the pathological response. 2024-10-22T06:22:57Z 2024-10-22T06:22:57Z 2024 info:eu-repo/semantics/article info:eu-repo/semantics/publishedVersion Yáñez-Bisbe L, Moya M, Rodríguez-Sinovas A, Ruiz-Meana M, Inserte J, Tajes M, et al. TRPV4 channels promote pathological, but not physiological, cardiac remodeling through the activation of calcineurin/NFAT and TRPC6. Int J Mol Sci. 2024 Jan 26;25(3):1541. DOI: 10.3390/ijms25031541 1422-0067 http://hdl.handle.net/10230/68279 http://dx.doi.org/10.3390/ijms25031541 eng Int J Mol Sci. 2024 Jan 26;25(3):1541 © 2024 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). http://creativecommons.org/licenses/by/4.0/ info:eu-repo/semantics/openAccess application/pdf application/pdf MDPI