[HTML][HTML] TRPC3-GEF-H1 axis mediates pressure overload-induced cardiac fibrosis

T Numaga-Tomita, N Kitajima, T Kuroda, A Nishimura… - Scientific reports, 2016 - nature.com
T Numaga-Tomita, N Kitajima, T Kuroda, A Nishimura, K Miyano, S Yasuda, K Kuwahara
Scientific reports, 2016nature.com
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 …
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.
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