Reference - Detail
| RRC ID | 47694 |
|---|---|
| Author | 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. |
| Title | TRPC3-GEF-H1 axis mediates pressure overload-induced cardiac fibrosis. |
| Journal | Sci Rep |
| 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. |
| Volume | 6 |
| Pages | 39383 |
| Published | 2016-12-19 |
| DOI | 10.1038/srep39383 |
| PII | srep39383 |
| PMID | 27991560 |
| PMC | PMC5171702 |
| MeSH | Animals Cells, Cultured Fibroblasts / metabolism Fibrosis / metabolism* Heart / physiology* Humans Male Mice Microtubules / metabolism Myocytes, Cardiac / metabolism NADPH Oxidases / metabolism Proteomics / methods Rats Rho Guanine Nucleotide Exchange Factors / metabolism* Signal Transduction / physiology TRPC Cation Channels / metabolism* Transforming Growth Factor beta / metabolism rhoA GTP-Binding Protein / metabolism |
| IF | 3.998 |
| Times Cited | 26 |
| WOS Category | BIOCHEMISTRY & MOLECULAR BIOLOGY |
| Altmetric score |
オルトメトリクス指標項目
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| The most frequently cited source | X(Twitter) |
| Total number of mentions | 18 |
| Altmetric score changes over past 6months | 0.0 |
| Resource | |
| Human and Animal Cells | 253G1(HPS0002) |