TRPV4 channels promote pathological, but not physiological, cardiac remodeling through the activation of calcineurin/NFAT and TRPC6

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• dc.contributor.author Yáñez Bisbe, Laia, 1993-
• dc.contributor.author Moya, Mar
• dc.contributor.author Rodríguez-Sinovas, Antonio
• dc.contributor.author Ruiz-Meana, Marisol
• dc.contributor.author Inserte, Javier
• dc.contributor.author Tajes Orduña, Marta
• dc.contributor.author Batlle, Montserrat
• dc.contributor.author Guasch, Eduard
• dc.contributor.author Mas Stachurska, Aleksandra
• dc.contributor.author Miró, Elisabet
• dc.contributor.author Rivas, Nuria
• dc.contributor.author Ferreira González, Ignacio
• dc.contributor.author Garcia-Elias Heras, Anna
• dc.contributor.author Benito Villabriga, Begoña
• dc.date.accessioned 2024-10-22T06:22:57Z
• dc.date.available 2024-10-22T06:22:57Z
• dc.date.issued 2024
• dc.description.abstract 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.
• dc.format.mimetype application/pdf
• dc.identifier.citation 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
• dc.identifier.doi http://dx.doi.org/10.3390/ijms25031541
• dc.identifier.issn 1422-0067
• dc.identifier.uri http://hdl.handle.net/10230/68279
• dc.language.iso eng
• dc.publisher MDPI
• dc.relation.ispartof Int J Mol Sci. 2024 Jan 26;25(3):1541
• dc.rights © 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/).
• dc.rights.accessRights info:eu-repo/semantics/openAccess
• dc.rights.uri http://creativecommons.org/licenses/by/4.0/
• dc.subject.keyword TRP
• dc.subject.keyword TRPC6
• dc.subject.keyword TRPV4
• dc.subject.keyword Calcium
• dc.subject.keyword Exercise
• dc.subject.keyword Heart failure
• dc.subject.keyword Mechanoreceptors
• dc.subject.keyword Mechanotransduction
• dc.subject.keyword Pathological remodeling
• dc.subject.keyword Physiological remodeling
• dc.title TRPV4 channels promote pathological, but not physiological, cardiac remodeling through the activation of calcineurin/NFAT and TRPC6
• dc.type info:eu-repo/semantics/article
• dc.type.version info:eu-repo/semantics/publishedVersion