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

Takuro Numaga-Tomita, Naoyuki Kitajima, Takuya Kuroda, Akiyuki Nishimura, Kei Miyano, Satoshi Yasuda, Koichiro Kuwahara, Yoji Sato, Tomomi Ide, Lutz Birnbaumer, Hideki Sumimoto, Yasuo Mori, Motohiro Nishida

Research output: Contribution to journalArticle

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Abstract

Structural cardiac remodeling, accompanying cytoskeletal reorganization of cardiac cells, is a major clinical outcome of diastolic heart failure. A highly local Ca 2+ 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 Ca 2+ influx as a cytoskeletal reorganizing signal under the conditions of the rhythmic Ca 2+ 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.

Original languageEnglish
Article number39383
JournalScientific reports
Volume6
DOIs
Publication statusPublished - Dec 19 2016

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Cardiac Myocytes
Fibrosis
Microtubules
Pressure
Fibroblasts
Rho Guanine Nucleotide Exchange Factors
Diastolic Heart Failure
Chemical Stimulation
rho GTP-Binding Proteins
Mechanical Stress
NADPH Oxidase
Transforming Growth Factors
Proteomics
Cell Membrane
Pharmacology

All Science Journal Classification (ASJC) codes

  • General

Cite this

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

In: Scientific reports, Vol. 6, 39383, 19.12.2016.

Research output: Contribution to journalArticle

Numaga-Tomita, T, Kitajima, N, Kuroda, T, Nishimura, A, Miyano, K, Yasuda, S, Kuwahara, K, Sato, Y, Ide, T, Birnbaumer, L, Sumimoto, H, Mori, Y & Nishida, M 2016, 'TRPC3-GEF-H1 axis mediates pressure overload-induced cardiac fibrosis', Scientific reports, vol. 6, 39383. https://doi.org/10.1038/srep39383
Numaga-Tomita T, Kitajima N, Kuroda T, Nishimura A, Miyano K, Yasuda S et al. TRPC3-GEF-H1 axis mediates pressure overload-induced cardiac fibrosis. Scientific reports. 2016 Dec 19;6. 39383. https://doi.org/10.1038/srep39383
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. / TRPC3-GEF-H1 axis mediates pressure overload-induced cardiac fibrosis. In: Scientific reports. 2016 ; Vol. 6.
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