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

Autores
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
Año de publicación
2016
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
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.
Fil: Numaga Tomita, Takuro. Graduate University for Advanced Studies; Japón. National Institutes of Natural Sciences; Japón
Fil: Kitajima, Naoyuki. Graduate University for Advanced Studies; Japón. Kyushu University; Japón
Fil: Kuroda, Takuya. National Institute of Health Sciences; Japón
Fil: Nishimura, Akiyuki. National Institutes of Natural Sciences; Japón. Graduate University for Advanced Studies; Japón
Fil: Miyano, Kei. Kyushu University; Japón
Fil: Yasuda, Satoshi. National Institute of Health Sciences; Japón
Fil: Kuwahara, Koichiro. Shinshu University; Japón
Fil: Sato, Yoji. Kyushu University; Japón. National Institute of Health Sciences; Japón
Fil: Ide, Tomomi. Kyushu University; Japón
Fil: Birnbaumer, Lutz. Pontificia Universidad Católica Argentina ; Argentina. National Institutes of Health; Estados Unidos
Fil: Sumimoto, Hideki. Kyushu University; Japón
Fil: Mori, Yasuo. Kyoto University; Japón
Fil: Nishida, Motohiro. Kyushu University; Japón. National Institutes of Natural Sciences; Japón. Graduate University for Advanced Studies; Japón
Materia
TRPC3
GEF-H1
Rho
Heart Failure
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/51651

id CONICETDig_0b6127e9220a9f5a0e75e2e7e2936763
oai_identifier_str oai:ri.conicet.gov.ar:11336/51651
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling TRPC3-GEF-H1 axis mediates pressure overload-induced cardiac fibrosisNumaga Tomita, TakuroKitajima, NaoyukiKuroda, TakuyaNishimura, AkiyukiMiyano, KeiYasuda, SatoshiKuwahara, KoichiroSato, YojiIde, TomomiBirnbaumer, LutzSumimoto, HidekiMori, YasuoNishida, MotohiroTRPC3GEF-H1RhoHeart Failurehttps://purl.org/becyt/ford/3.1https://purl.org/becyt/ford/3Structural 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.Fil: Numaga Tomita, Takuro. Graduate University for Advanced Studies; Japón. National Institutes of Natural Sciences; JapónFil: Kitajima, Naoyuki. Graduate University for Advanced Studies; Japón. Kyushu University; JapónFil: Kuroda, Takuya. National Institute of Health Sciences; JapónFil: Nishimura, Akiyuki. National Institutes of Natural Sciences; Japón. Graduate University for Advanced Studies; JapónFil: Miyano, Kei. Kyushu University; JapónFil: Yasuda, Satoshi. National Institute of Health Sciences; JapónFil: Kuwahara, Koichiro. Shinshu University; JapónFil: Sato, Yoji. Kyushu University; Japón. National Institute of Health Sciences; JapónFil: Ide, Tomomi. Kyushu University; JapónFil: Birnbaumer, Lutz. Pontificia Universidad Católica Argentina ; Argentina. National Institutes of Health; Estados UnidosFil: Sumimoto, Hideki. Kyushu University; JapónFil: Mori, Yasuo. Kyoto University; JapónFil: Nishida, Motohiro. Kyushu University; Japón. National Institutes of Natural Sciences; Japón. Graduate University for Advanced Studies; JapónNature Publishing Group2016-12info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/51651Numaga Tomita, Takuro; Kitajima, Naoyuki; Kuroda, Takuya; Nishimura, Akiyuki; Miyano, Kei; et al.; TRPC3-GEF-H1 axis mediates pressure overload-induced cardiac fibrosis; Nature Publishing Group; Scientific Reports; 6; 12-2016; 1-15; 393832045-2322CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/https://www.nature.com/articles/srep39383info:eu-repo/semantics/altIdentifier/doi/10.1038/srep39383info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-10-22T11:42:06Zoai:ri.conicet.gov.ar:11336/51651instacron:CONICETInstitucionalhttp://ri.conicet.gov.ar/Organismo científico-tecnológicoNo correspondehttp://ri.conicet.gov.ar/oai/requestdasensio@conicet.gov.ar; lcarlino@conicet.gov.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:34982025-10-22 11:42:06.369CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv TRPC3-GEF-H1 axis mediates pressure overload-induced cardiac fibrosis
title TRPC3-GEF-H1 axis mediates pressure overload-induced cardiac fibrosis
spellingShingle TRPC3-GEF-H1 axis mediates pressure overload-induced cardiac fibrosis
Numaga Tomita, Takuro
TRPC3
GEF-H1
Rho
Heart Failure
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
dc.creator.none.fl_str_mv 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 Numaga Tomita, Takuro
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_role author
author2 Kitajima, Naoyuki
Kuroda, Takuya
Nishimura, Akiyuki
Miyano, Kei
Yasuda, Satoshi
Kuwahara, Koichiro
Sato, Yoji
Ide, Tomomi
Birnbaumer, Lutz
Sumimoto, Hideki
Mori, Yasuo
Nishida, Motohiro
author2_role author
author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv TRPC3
GEF-H1
Rho
Heart Failure
topic TRPC3
GEF-H1
Rho
Heart Failure
purl_subject.fl_str_mv https://purl.org/becyt/ford/3.1
https://purl.org/becyt/ford/3
dc.description.none.fl_txt_mv 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.
Fil: Numaga Tomita, Takuro. Graduate University for Advanced Studies; Japón. National Institutes of Natural Sciences; Japón
Fil: Kitajima, Naoyuki. Graduate University for Advanced Studies; Japón. Kyushu University; Japón
Fil: Kuroda, Takuya. National Institute of Health Sciences; Japón
Fil: Nishimura, Akiyuki. National Institutes of Natural Sciences; Japón. Graduate University for Advanced Studies; Japón
Fil: Miyano, Kei. Kyushu University; Japón
Fil: Yasuda, Satoshi. National Institute of Health Sciences; Japón
Fil: Kuwahara, Koichiro. Shinshu University; Japón
Fil: Sato, Yoji. Kyushu University; Japón. National Institute of Health Sciences; Japón
Fil: Ide, Tomomi. Kyushu University; Japón
Fil: Birnbaumer, Lutz. Pontificia Universidad Católica Argentina ; Argentina. National Institutes of Health; Estados Unidos
Fil: Sumimoto, Hideki. Kyushu University; Japón
Fil: Mori, Yasuo. Kyoto University; Japón
Fil: Nishida, Motohiro. Kyushu University; Japón. National Institutes of Natural Sciences; Japón. Graduate University for Advanced Studies; Japón
description 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.
publishDate 2016
dc.date.none.fl_str_mv 2016-12
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
http://purl.org/coar/resource_type/c_6501
info:ar-repo/semantics/articulo
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/11336/51651
Numaga Tomita, Takuro; Kitajima, Naoyuki; Kuroda, Takuya; Nishimura, Akiyuki; Miyano, Kei; et al.; TRPC3-GEF-H1 axis mediates pressure overload-induced cardiac fibrosis; Nature Publishing Group; Scientific Reports; 6; 12-2016; 1-15; 39383
2045-2322
CONICET Digital
CONICET
url http://hdl.handle.net/11336/51651
identifier_str_mv Numaga Tomita, Takuro; Kitajima, Naoyuki; Kuroda, Takuya; Nishimura, Akiyuki; Miyano, Kei; et al.; TRPC3-GEF-H1 axis mediates pressure overload-induced cardiac fibrosis; Nature Publishing Group; Scientific Reports; 6; 12-2016; 1-15; 39383
2045-2322
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/url/https://www.nature.com/articles/srep39383
info:eu-repo/semantics/altIdentifier/doi/10.1038/srep39383
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
dc.publisher.none.fl_str_mv Nature Publishing Group
publisher.none.fl_str_mv Nature Publishing Group
dc.source.none.fl_str_mv reponame:CONICET Digital (CONICET)
instname:Consejo Nacional de Investigaciones Científicas y Técnicas
reponame_str CONICET Digital (CONICET)
collection CONICET Digital (CONICET)
instname_str Consejo Nacional de Investigaciones Científicas y Técnicas
repository.name.fl_str_mv CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicas
repository.mail.fl_str_mv dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar
_version_ 1846782105138233344
score 12.982451