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
• Fuente: Scientific Reports. 2016;6:39383
• Materia: FIBROSIS; CORAZON; CRECIMIENTO; CELULAS
• Institución: Pontificia Universidad Católica Argentina

Fil: Numaga-Tomita, Takuro. National Institute for Physiological Sciences. Okazaki Institute for Integrative Bioscience. Division of Cardiocirculatory Signaling; Japón
Fil: Numaga-Tomita, Takuro. The Graduate University for Advanced Studies. School of Life Science. Department of Physiological Sciences; Japón
Fil: Kitajima, Naoyuki. National Institute for Physiological Sciences. Okazaki Institute for Integrative Bioscience. Division of Cardiocirculatory Signaling; Japón
Fil: Kitajima, Naoyuki. Kyushu University. Graduate School of Pharmaceutical Sciences. Department of Translational Pharmaceutical Sciences; Japón
Fil: Kuroda, Takuya. National Institute of Health Sciences. Division of Cell-Based Therapeutic Products; Japón
Fil: Nishimura, Akiyuki. National Institute for Physiological Sciences. Okazaki Institute for Integrative Bioscience. Division of Cardiocirculatory Signaling; Japón
Fil: Nishimura, Akiyuki. The Graduate University for Advanced Studies. School of Life Science. Department of Physiological Sciences; Japón
Fil: Miyano, Kei. Kyushu University. Graduate School of Medical Sciences. Department of Biochemistry; Japón
Fil: Yasuda, Satoshi. National Institute of Health Sciences. Division of Cell-Based Therapeutic Products; Japón
Fil: Kuwahara, Koichiro. Shinshu University. School of Medicine. Department of Cardiovascular Medicine; Japón
Fil: Sato, Yoji. Kyushu University. Graduate School of Pharmaceutical Sciences. Department of Translational Pharmaceutical Sciences; Japón
Fil: Sato, Yoji. National Institute of Health Sciences. Division of Cell-Based Therapeutic Products; Japón
Fil: Ide, Tomomi. Kyushu University. Graduate School of Medical Sciences. Department of Cardiovascular Medicine; Argentina
Fil: Birnbaumer, Lutz. Pontificia Universidad Católica Argentina. Facultad de Ciencias Médicas. Instituto de Investigaciones Biomédicas; Argentina
Fil: Birnbaumer, Lutz. National Institute of Environmental Health Sciences. Neurobiology Laboratory; Estados Unidos
Fil: Sumimoto, Hideki. Kyushu University. Graduate School of Medical Sciences. Department of Biochemistry; Japón
Fil: Mori, Yasuo. Kyoto University. Graduate School of Engineering. Department of Synthetic Chemistry and Biological Chemistry; Japón
Fil: Nishida, Motohiro. National Institute for Physiological Sciences. Okazaki Institute for Integrative Bioscience. Division of Cardiocirculatory Signaling; Japón
Fil: Nishida, Motohiro. The Graduate University for Advanced Studies. School of Life Science. Department of Physiological Sciences; Japón
Fil: Nishida, Motohiro. Kyushu University. Graduate School of Pharmaceutical Sciences. Department of Translational Pharmaceutical Sciences; Japón
Fil: Nishida, Motohiro. Precursory Research for Embryonic Science and Technology; Japón
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.