TRPC3-GEF-H1 axis mediates pressure overload-induced cardiac fibrosis

Abstract: Structural cardiac remodeling, accompanying cytoskeletal reorganization of cardiac cells, is a major clinical outcome of diastolic heart failure. A highly local Ca2+ influx across the plasma membrane has been suggested to code signals to induce Rho GTPase-mediated fibrosis, but it is obscu...

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Autores principales: Numaga-Tomita, Takuro, Kitajima, Naoyuki, Kuroda, Takuya, Nishimura, Akiyuki, Miyano, Kei, Yasuda, Satoshi, Kuwahara, Koichiro, Sato, Yoji, Ide, Tomomi, Birnbaumer, Lutz, Sumimoto, Hideki, Mori, Yasuo, Nishida, Motohiro
Formato: Artículo
Lenguaje:Inglés
Publicado: Nature Research 2019
Materias:
FIBROSIS
CORAZON
CRECIMIENTO
CELULAS
Acceso en línea:https://repositorio.uca.edu.ar/handle/123456789/8746
Aporte de:
Repositorio Institucional de la Universidad Católica Argentina (UCA) de Universidad Católica Argentina
id I33-R139123456789-8746
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 FIBROSIS
CORAZON
CRECIMIENTO
CELULAS
spellingShingle FIBROSIS
CORAZON
CRECIMIENTO
CELULAS
Numaga-Tomita, Takuro
Kitajima, Naoyuki
Kuroda, Takuya
Nishimura, Akiyuki
Miyano, Kei
Yasuda, Satoshi
Kuwahara, Koichiro
Sato, Yoji
Ide, Tomomi
Birnbaumer, Lutz
Sumimoto, Hideki
Mori, Yasuo
Nishida, Motohiro
TRPC3-GEF-H1 axis mediates pressure overload-induced cardiac fibrosis
topic_facet FIBROSIS
CORAZON
CRECIMIENTO
CELULAS
description Abstract: Structural cardiac remodeling, accompanying cytoskeletal reorganization of cardiac cells, is a major clinical outcome of diastolic heart failure. A highly local Ca2+ influx across the plasma membrane has been suggested to code signals to induce Rho GTPase-mediated fibrosis, but it is obscure how the heart specifically decodes the local Ca2+ influx as a cytoskeletal reorganizing signal under the conditions of the rhythmic Ca2+ handling required for pump function. We found that an inhibition of transient receptor potential canonical 3 (TRPC3) channel activity exhibited resistance to Rho-mediated maladaptive fibrosis in pressure-overloaded mouse hearts. Proteomic analysis revealed that microtubule-associated Rho guanine nucleotide exchange factor, GEF-H1, participates in TRPC3-mediated RhoA activation induced by mechanical stress in cardiomyocytes and transforming growth factor (TGF) β stimulation in cardiac fibroblasts. We previously revealed that TRPC3 functionally interacts with microtubule-associated NADPH oxidase (Nox) 2, and inhibition of Nox2 attenuated mechanical stretch-induced GEF-H1 activation in cardiomyocytes. Finally, pharmacological TRPC3 inhibition significantly suppressed fibrotic responses in human cardiomyocytes and cardiac fibroblasts. These results strongly suggest that microtubule-localized TRPC3-GEF-H1 axis mediates fibrotic responses commonly in cardiac myocytes and fibroblasts induced by physico-chemical stimulation.
format Artículo
author Numaga-Tomita, Takuro
Kitajima, Naoyuki
Kuroda, Takuya
Nishimura, Akiyuki
Miyano, Kei
Yasuda, Satoshi
Kuwahara, Koichiro
Sato, Yoji
Ide, Tomomi
Birnbaumer, Lutz
Sumimoto, Hideki
Mori, Yasuo
Nishida, Motohiro
author_facet Numaga-Tomita, Takuro
Kitajima, Naoyuki
Kuroda, Takuya
Nishimura, Akiyuki
Miyano, Kei
Yasuda, Satoshi
Kuwahara, Koichiro
Sato, Yoji
Ide, Tomomi
Birnbaumer, Lutz
Sumimoto, Hideki
Mori, Yasuo
Nishida, Motohiro
author_sort Numaga-Tomita, Takuro
title TRPC3-GEF-H1 axis mediates pressure overload-induced cardiac fibrosis
title_short TRPC3-GEF-H1 axis mediates pressure overload-induced cardiac fibrosis
title_full TRPC3-GEF-H1 axis mediates pressure overload-induced cardiac fibrosis
title_fullStr TRPC3-GEF-H1 axis mediates pressure overload-induced cardiac fibrosis
title_full_unstemmed TRPC3-GEF-H1 axis mediates pressure overload-induced cardiac fibrosis
title_sort trpc3-gef-h1 axis mediates pressure overload-induced cardiac fibrosis
publisher Nature Research
publishDate 2019
url https://repositorio.uca.edu.ar/handle/123456789/8746
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