RRC ID 47694
著者 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.
タイトル TRPC3-GEF-H1 axis mediates pressure overload-induced cardiac fibrosis.
ジャーナル 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.
巻・号 6
ページ 39383
公開日 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
引用数 26
WOS 分野 BIOCHEMISTRY & MOLECULAR BIOLOGY
リソース情報
ヒト・動物細胞 253G1(HPS0002)