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Sci Rep. 2016 Dec 19;6:39383. doi: 10.1038/srep39383.

TRPC3-GEF-H1 axis mediates pressure overload-induced cardiac fibrosis.

Author information

1
Division of Cardiocirculatory Signaling, Okazaki Institute for Integrative Bioscience (National Institute for Physiological Sciences), National Institutes of Natural Sciences, Aichi 444-8787, Japan.
2
Department of Physiological Sciences, SOKENDAI (School of Life Science, The Graduate University for Advanced Studies), Aichi 444-8787, Japan.
3
Department of Translational Pharmaceutical Sciences, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka 812-8582, Japan.
4
Division of Cell-Based Therapeutic Products, National Institute of Health Sciences, Setagaya, Tokyo 158-8501, Japan.
5
Department of Biochemistry, Kyushu University Graduate School of Medical Sciences, Fukuoka 812-8582, Japan.
6
Department of Cardiovascular Medicine Shinshu University School of Medicine, Nagano 390-8621, Japan.
7
Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan.
8
Laboratory of Neuroscience, NIEHS, NIH, Research Triangle Park, NC 27709, USA.
9
Institute for Biomedical Research (BIOMED), Catholic University of Argentina, C1107AFF Buenos Aires, Argentina.
10
Department of Synthetic Chemistry and Biological Chemistry, Graduate School of Engineering, Kyoto University, Kyoto 615-8510, Japan.
11
PRESTO, JST, 4-1-8 Honcho, Kawaguchi, Saitama 332-0012, Japan.

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.

PMID:
27991560
PMCID:
PMC5171702
DOI:
10.1038/srep39383
[Indexed for MEDLINE]
Free PMC Article

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