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

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.

TRPC3-Nox2 complex mediates doxorubicin-induced myocardial atrophy

“…We also found that voluntary exercise causes hypertrophy with preserved cardiac contractility by enhancing LV compliance and flexibility through destabilization of Nox2 (Figure 7, G-J, and Table 7). Taken together with our earlier observations made in a pressure-overloaded mouse heart model (20,27), our present findings, to our knowledge, provide a new concept that a TRPC3-Nox2 complex functions as a common major risk factor for chronic heart failure, driving pathological cardiac remodeling. Furthermore, they suggest that, by suppressing Nox2-mediated ROS production in cardiomyocytes, TRPC3 inhibition may be an effective strategy for reducing the risk of DOX-induced heart failure ( Figure 7K).…”

“…In particular, two TRP canonical (TRPC) subfamily members, TRPC3 and TRPC6, reportedly participate in the development of pathological hypertrophy caused by neurohumoral factors (22,23) and mechanical stress (24)(25)(26). Our recent studies using TRPC-KO mice revealed that TRPC3, but not TRPC6, functions as a positive regulator of ROS, leading to induction of mechanical stress-induced maladaptive fibrosis (15,20,27). TRPC3 interacts with Nox2 via TRPC3-specific C-terminal sites, thereby protecting Nox2 from proteasome-dependent degradation and amplifying Ca 2+ -dependent Nox2 activation through TRPC3-mediated background Ca 2+ entry (20).…”

Protective mechanism of SIRT1 on Hcy‐induced atrial fibrosis mediated by TRPC3

“…Next, we take atrial mouse fibroblasts as the cell model. Pyr-10, an selective inhibitor of TRPC3, could markedly block the DAG-mediated TRPC3 signalling pathway, controlling the extent of fibrosis in the cell models33,34 ; In our study, it was observed the lower protein levels of TRPC3 and TGF-βin Hcy+Pyr-10 group, compared to Hcy group, which implied that Pyr-10 abolished the effect of Hcy-mediated atrial fibrosis via the inhibition of DAG-TRPC3 signalling pathway. Moreover, it was attenuated Hcy-induced atrial fibrosis (Figure 5B,D) and reduced the proliferation of fibroblasts in TRPC3-shRNA-transfected fibroblasts (…”

Light-Mediated Control over TRPC3-Mediated NFAT Signaling

“…TRPC3/6/7 pore complexes are able to sense various stress signals, and are primarily regulated by phospholipase C (PLC)-derived lipid mediators [6][7][8], and TRPC3 stands out for its distinct constitutive activity, which is reportedly governed by its glycosylation state [9]. TRPC3 as well as its closest relative TRPC6 have been identified to trigger Ca 2+ -dependent nuclear factor of activated T-cells (NFAT) nuclear translocation in native cardiovascular cells including myocytes [10][11][12] as well as fibroblasts [13]. Pharmacological abrogation of TRPC3/6 function was suggested as a potential therapeutic strategy for cardiovascular remodeling and heart failure prevention [14].…”