Artículo
TRPC3-GEF-H1 axis mediates pressure overload-induced cardiac fibrosis
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
Fecha de publicación:
12/2016
Editorial:
Nature Publishing Group
Revista:
Scientific Reports
e-ISSN:
2045-2322
Idioma:
Inglés
Tipo de recurso:
Artículo publicado
Clasificación temática:
Resumen
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.
Palabras clave:
Trpc3
,
Gef-H1
,
Rho
,
Heart Failure
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Identificadores
Colecciones
Articulos(OCA HOUSSAY)
Articulos de OFICINA DE COORDINACION ADMINISTRATIVA HOUSSAY
Articulos de OFICINA DE COORDINACION ADMINISTRATIVA HOUSSAY
Citación
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
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