TRPC3-GEF-H1 axis mediates pressure overload-induced cardiac fibrosis
| Autor: | Koichiro Kuwahara, Takuya Kuroda, Yasuo Mori, Satoshi Yasuda, Lutz Birnbaumer, Hideki Sumimoto, Takuro Numaga-Tomita, Akiyuki Nishimura, Motohiro Nishida, Yoji Sato, Tomomi Ide, Naoyuki Kitajima, Kei Miyano |
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| Jazyk: | angličtina |
| Rok vydání: | 2016 |
| Předmět: |
Male
Proteomics 0301 basic medicine RHOA Cardiac fibrosis Microtubules TRPC3 Mice CORAZON 0302 clinical medicine Transforming Growth Factor beta Fibrosis Myocyte FIBROSIS Myocytes Cardiac Cells Cultured Multidisciplinary NADPH oxidase biology Chemistry Heart purl.org/becyt/ford/3.1 [https] Cell biology Medicina Básica purl.org/becyt/ford/3 [https] Signal Transduction CIENCIAS MÉDICAS Y DE LA SALUD Inmunología Heart failure Article 03 medical and health sciences Rho medicine Animals Humans CRECIMIENTO GEF-H1 TRPC Cation Channels Pressure overload Heart Failure CELULAS NADPH Oxidases Fibroblasts medicine.disease Rats 030104 developmental biology biology.protein rhoA GTP-Binding Protein Ion channel signalling Rho Guanine Nucleotide Exchange Factors 030217 neurology & neurosurgery Transforming growth factor |
| Zdroj: | Scientific Reports. 2016;6:39383 Repositorio Institucional (UCA) Pontificia Universidad Católica Argentina instacron:UCA Scientific Reports CONICET Digital (CONICET) Consejo Nacional de Investigaciones Científicas y Técnicas instacron:CONICET |
| Popis: | 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 Article SCIENTIFIC REPORTS. 6: 39383(2016) |
| Databáze: | OpenAIRE |
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