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
- Institución
- Consejo Nacional de Investigaciones Científicas y Técnicas
- OAI Identificador
- oai:ri.conicet.gov.ar:11336/51651
Ver los metadatos del registro completo
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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 |
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12.982451 |