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Título : TRPC3-GEF-H1 axis mediates pressure overload-induced cardiac fibrosis
Autor : 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 : 2016
Editorial : Nature Research
Cita : Numaga-Tomita T, Kitajima N, Kuroda T, et al. TRPC3-GEF-H1 axis mediates pressure overload-induced cardiac fibrosis [en línea]. Scientific Reports. 2016;6:39383. doi:10.1038/srep39383 Disponible en:
Resumen : 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.
ISSN : 2045-2322
Disciplina: MEDICINA
DOI: 10.1038/srep39383
Derechos: Acceso Abierto
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