TRPV4 Channels Promote Pathological, but Not Physiological, Cardiac Remodeling through the Activation of Calcineurin/NFAT and TRPC6
Yáñez-Bisbe, Laia (Hospital Universitari Vall d'Hebron. Institut de Recerca)
Moya, Mar (Hospital Universitari Vall d'Hebron. Institut de Recerca)
Rodríguez-Sinovas, Antonio (Hospital Universitari Vall d'Hebron. Institut de Recerca)
Ruiz Meana, Marisol (Hospital Universitari Vall d'Hebron. Institut de Recerca)
Inserte, Javier (Hospital Universitari Vall d'Hebron. Institut de Recerca)
Tajes, Marta (Institut d'Investigació Biomèdica de Bellvitge)
Batlle, Montserrat (Institut d'Investigacions Biomèdiques August Pi i Sunyer)
Guasch, Eduard (Institut d'Investigacions Biomèdiques August Pi i Sunyer)
Mas-Stachurska, Aleksandra (Hospital del Mar (Barcelona, Catalunya))
Miró, Elisabet (Hospital Universitari Vall d'Hebron. Institut de Recerca)
Rivas, Nuria (Hospital Universitari Vall d'Hebron)
Ferreira-Gonzalez, Ignacio (Universitat Autònoma de Barcelona. Departament de Medicina)
Garcia-Elias, Anna (ASCIRES-CETIR Biomedic Group (Barcelona))
Benito, Begoña (Universitat Autònoma de Barcelona. Departament de Medicina)

Fecha:	2024
Resumen:	TRPV4 channels, which respond to mechanical activation by permeating Ca 2+ 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 Ca 2+ -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, Ca 2+ 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 Ca 2+ 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 Ca 2+ -dependent CN/NFATc3 signaling. These results pose TRPV4 as a primary mediator of the pathological response.
Ayudas:	Ministerio de Economía y Competitividad PI16/00619
Derechos:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Lengua:	Anglès
Documento:	Article ; recerca ; Versió publicada
Materia:	TRPV4 ; TRPC6 ; Calcium ; Mechanotransduction ; Mechanoreceptors ; TRP ; Pathological remodeling ; Heart failure ; Physiological remodeling ; Exercise
Publicado en:	International journal of molecular sciences, Vol. 25 (january 2024) , ISSN 1422-0067

DOI: 10.3390/ijms25031541
PMID: 38338818

20 p, 3.8 MB

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