Transient Receptor Potential Canonical 3 and nuclear factor of activated T cells C3 signaling pathway critically regulates myocardial fibrosis

Abstract: Aims: Cardiac fibroblasts (CFs) are emerging as major contributors to myocardial fibrosis (MF), a final common pathway of many etiologies of heart disease. Here, we studied the functional relevance of transient receptor potential canonical 3 (TRPC3) channels and nuclear factor of activat...

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Autores principales: Saliba, Youakim, Jebara, Victor, Hajal, Joelle, Maroun, Richard, Chacar, Stéphanie, Smayra, Viviane, Abramowitz, Joel, Birnbaumer, Lutz, Farès, Nassim
Formato: Artículo
Lenguaje:Inglés
Publicado: Mary Ann Liebert 2020
Materias:
TRPC3
CALCIO
FIBROSIS
POLIFENOLES
CARDIOPATIAS
TRATAMIENTO MEDICO
Acceso en línea:https://repositorio.uca.edu.ar/handle/123456789/9853
Aporte de:
Repositorio Institucional de la Universidad Católica Argentina (UCA) de Universidad Católica Argentina
id I33-R139123456789-9853
record_format dspace
institution Universidad Católica Argentina
institution_str I-33
repository_str R-139
collection Repositorio Institucional de la Universidad Católica Argentina (UCA)
language Inglés
topic TRPC3
CALCIO
FIBROSIS
POLIFENOLES
CARDIOPATIAS
TRATAMIENTO MEDICO
spellingShingle TRPC3
CALCIO
FIBROSIS
POLIFENOLES
CARDIOPATIAS
TRATAMIENTO MEDICO
Saliba, Youakim
Jebara, Victor
Hajal, Joelle
Maroun, Richard
Chacar, Stéphanie
Smayra, Viviane
Abramowitz, Joel
Birnbaumer, Lutz
Farès, Nassim
Transient Receptor Potential Canonical 3 and nuclear factor of activated T cells C3 signaling pathway critically regulates myocardial fibrosis
topic_facet TRPC3
CALCIO
FIBROSIS
POLIFENOLES
CARDIOPATIAS
TRATAMIENTO MEDICO
description Abstract: Aims: Cardiac fibroblasts (CFs) are emerging as major contributors to myocardial fibrosis (MF), a final common pathway of many etiologies of heart disease. Here, we studied the functional relevance of transient receptor potential canonical 3 (TRPC3) channels and nuclear factor of activated T cells c3 (NFATc3) signaling in rodent and human ventricular CFs, and whether their modulation would limit MF. Results: A positive feedback loop between TRPC3 and NFATc3 drove a rat ventricular CF fibrotic phenotype. In these cells, polyphenols (extract of grape pomace polyphenol [P.E.]) decreased basal and angiotensin II-mediated Ca2+ entries through a direct modulation of TRPC3 channels and subsequently NFATc3 signaling, abrogating myofibroblast differentiation, fibrosis and inflammation, as well as an oxidative stress-associated phenotype. N(ω)-nitro-l-arginine methyl ester (l-NAME) hypertensive rats developed coronary perivascular, sub-epicardial, and interstitial fibrosis with induction of embryonic epicardial progenitor transcription factors in activated CFs. P.E. treatment reduced ventricular CF activation by modulating the TRPC3-NFATc3 pathway, and it ameliorated echocardiographic parameters, cardiac stress markers, and MF in l-NAME hypertensive rats independently of blood pressure regulation. Further, genetic deletion (TRPC3−/−) and pharmacological channel blockade with N-[4-[3,5-Bis(trifluoromethyl)-1H-pyrazol-1-yl]phenyl]-4-methyl-benzenesulfonamide (Pyr10) blunted ventricular CF activation and MF in l-NAME hypertensive mice. Finally, TRPC3 was present in human ventricular CFs and upregulated in MF, whereas pharmacological modulation of TRPC3-NFATc3 decreased proliferation and collagen secretion. Innovation and Conclusion: We demonstrate that TRPC3-NFATc3 signaling is modulated by P.E. and critically regulates ventricular CF phenotype and MF. These findings strongly argue for P.E., through TRPC3 targeting, as potential and interesting therapeutics for MF management.
format Artículo
author Saliba, Youakim
Jebara, Victor
Hajal, Joelle
Maroun, Richard
Chacar, Stéphanie
Smayra, Viviane
Abramowitz, Joel
Birnbaumer, Lutz
Farès, Nassim
author_facet Saliba, Youakim
Jebara, Victor
Hajal, Joelle
Maroun, Richard
Chacar, Stéphanie
Smayra, Viviane
Abramowitz, Joel
Birnbaumer, Lutz
Farès, Nassim
author_sort Saliba, Youakim
title Transient Receptor Potential Canonical 3 and nuclear factor of activated T cells C3 signaling pathway critically regulates myocardial fibrosis
title_short Transient Receptor Potential Canonical 3 and nuclear factor of activated T cells C3 signaling pathway critically regulates myocardial fibrosis
title_full Transient Receptor Potential Canonical 3 and nuclear factor of activated T cells C3 signaling pathway critically regulates myocardial fibrosis
title_fullStr Transient Receptor Potential Canonical 3 and nuclear factor of activated T cells C3 signaling pathway critically regulates myocardial fibrosis
title_full_unstemmed Transient Receptor Potential Canonical 3 and nuclear factor of activated T cells C3 signaling pathway critically regulates myocardial fibrosis
title_sort transient receptor potential canonical 3 and nuclear factor of activated t cells c3 signaling pathway critically regulates myocardial fibrosis
publisher Mary Ann Liebert
publishDate 2020
url https://repositorio.uca.edu.ar/handle/123456789/9853
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