title: TRPC3-GEF-H1 axis mediates pressure overload-induced cardiac fibrosis.
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.
authors.affiliation: Division of Cardiocirculatory Signaling, Okazaki Institute for Integrative Bioscience (National Institute for Physiological Sciences), National Institutes of Natural Sciences, Aichi 444-8787, Japan.|Department of Physiological Sciences, SOKENDAI (School of Life Science, The Graduate University for Advanced Studies), Aichi 444-8787, Japan.
authors.forename: Takuro
authors.initials: T
authors.lastname: Numaga-Tomita
authors.affiliation: Division of Cardiocirculatory Signaling, Okazaki Institute for Integrative Bioscience (National Institute for Physiological Sciences), National Institutes of Natural Sciences, Aichi 444-8787, Japan.|Department of Translational Pharmaceutical Sciences, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka 812-8582, Japan.
authors.forename: Naoyuki
authors.initials: N
authors.lastname: Kitajima
authors.affiliation: Division of Cell-Based Therapeutic Products, National Institute of Health Sciences, Setagaya, Tokyo 158-8501, Japan.
authors.forename: Takuya
authors.initials: T
authors.lastname: Kuroda
authors.affiliation: Division of Cardiocirculatory Signaling, Okazaki Institute for Integrative Bioscience (National Institute for Physiological Sciences), National Institutes of Natural Sciences, Aichi 444-8787, Japan.|Department of Physiological Sciences, SOKENDAI (School of Life Science, The Graduate University for Advanced Studies), Aichi 444-8787, Japan.
authors.forename: Akiyuki
authors.initials: A
authors.lastname: Nishimura
authors.affiliation: Department of Biochemistry, Kyushu University Graduate School of Medical Sciences, Fukuoka 812-8582, Japan.
authors.forename: Kei
authors.initials: K
authors.lastname: Miyano
authors.affiliation: Division of Cell-Based Therapeutic Products, National Institute of Health Sciences, Setagaya, Tokyo 158-8501, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Yasuda
authors.affiliation: Department of Cardiovascular Medicine Shinshu University School of Medicine, Nagano 390-8621, Japan.
authors.forename: Koichiro
authors.initials: K
authors.lastname: Kuwahara
authors.affiliation: Department of Translational Pharmaceutical Sciences, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka 812-8582, Japan.|Division of Cell-Based Therapeutic Products, National Institute of Health Sciences, Setagaya, Tokyo 158-8501, Japan.
authors.forename: Yoji
authors.initials: Y
authors.lastname: Sato
authors.affiliation: Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan.
authors.forename: Tomomi
authors.initials: T
authors.lastname: Ide
authors.affiliation: Laboratory of Neuroscience, NIEHS, NIH, Research Triangle Park, NC 27709, USA.|Institute for Biomedical Research (BIOMED), Catholic University of Argentina, C1107AFF Buenos Aires, Argentina.
authors.forename: Lutz
authors.initials: L
authors.lastname: Birnbaumer
authors.affiliation: Department of Biochemistry, Kyushu University Graduate School of Medical Sciences, Fukuoka 812-8582, Japan.
authors.forename: Hideki
authors.initials: H
authors.lastname: Sumimoto
authors.affiliation: Department of Synthetic Chemistry and Biological Chemistry, Graduate School of Engineering, Kyoto University, Kyoto 615-8510, Japan.
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Mori
authors.affiliation: Division of Cardiocirculatory Signaling, Okazaki Institute for Integrative Bioscience (National Institute for Physiological Sciences), National Institutes of Natural Sciences, Aichi 444-8787, Japan.|Department of Physiological Sciences, SOKENDAI (School of Life Science, The Graduate University for Advanced Studies), Aichi 444-8787, Japan.|Department of Translational Pharmaceutical Sciences, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka 812-8582, Japan.|PRESTO, JST, 4-1-8 Honcho, Kawaguchi, Saitama 332-0012, Japan.
authors.forename: Motohiro
authors.initials: M
authors.lastname: Nishida
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D005347:Fibroblasts / Q000378:metabolism; D005355:Fibrosis / Q000378:metabolism*; D006321:Heart / Q000502:physiology*; D006801:Humans; D008297:Male; D051379:Mice; D008870:Microtubules / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000378:metabolism; D019255:NADPH Oxidases / Q000378:metabolism; D040901:Proteomics / Q000379:methods; D051381:Rats; D064067:Rho Guanine Nucleotide Exchange Factors / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D050052:TRPC Cation Channels / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000378:metabolism; D020742:rhoA GTP-Binding Protein / Q000378:metabolism
chemical_list: D064067:Rho Guanine Nucleotide Exchange Factors; D050052:TRPC Cation Channels; C104603:TRPC3 cation channel; D016212:Transforming Growth Factor beta; D019255:NADPH Oxidases; D020742:rhoA GTP-Binding Protein