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ijms-25-01541.pdf (3.76 MB)

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2024-01-26

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cc by (c) Yáñez Bisbe, Laia et al., 2024
Si us plau utilitzeu sempre aquest identificador per citar o enllaçar aquest document: https://hdl.handle.net/2445/208403

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

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https://doi.org/10.3390/ijms25031541

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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.

Matèries

Insuficiència cardíaca, Ratolins transgènics

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Heart Failure, Mice, Transgenic

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Articles publicats en revistes (Institut d'lnvestigació Biomèdica de Bellvitge (IDIBELL))
Articles publicats en revistes (IDIBAPS: Institut d'investigacions Biomèdiques August Pi i Sunyer)

Citació

YÁÑEZ BISBE, Laia, MOYA, Mar, RODRÍGUEZ SINOVAS, Antonio, RUIZ MEANA, Marisol, INSERTE, Javier, TAJES ORDUÑA, Marta, BATLLE, Montserrat, GUASCH I CASANY, Eduard, MAS STACHURSKA, Aleksandra, MIRÓ, Elisabet, RIVAS, Nuria, FERREIRA GONZÁLEZ, Ignacio, GARCIA ELIAS, Anna, BENITO, Begoña. TRPV4 Channels Promote Pathological, but Not Physiological, Cardiac Remodeling through the Activation of Calcineurin/NFAT and TRPC6. _International Journal of Molecular Sciences_. 2024. Vol. 25, núm. 3, pàgs. 1541. [consulta: 9 de abril de 2026]. ISSN: 1422-0067. [Disponible a: https://hdl.handle.net/2445/208403]

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