TRPV4 Channels Promote Pathological, but Not Physiological, Cardiac Remodeling through the Activation of Calcineurin/NFAT and TRPC6

• Published in: International journal of molecular sciences Vol. 25; no. 3; p. 1541
• Main Authors: Yáñez-Bisbe, Laia, Moya, Mar, Rodríguez-Sinovas, Antonio, Ruiz-Meana, Marisol, Inserte, Javier, Tajes, Marta, Batlle, Montserrat, Guasch, Eduard, Mas-Stachurska, Aleksandra, Miró, Elisabet, Rivas, Nuria, Ferreira González, Ignacio, Garcia-Elias, Anna, Benito, Begoña
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 01.02.2024
• Subjects: Collagen; Fitness training programs; Gene expression; Heart; Ischemia; Kinases; Physiology; Protein expression; Proteins; Massachusetts; Spain; heart failure; TRP; TRPC6; calcium; TRPV4; mechanotransduction; exercise; mechanoreceptors; pathological remodeling; physiological remodeling
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms25031541

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.