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.
Highlights
Cardiac fibrosis, characterized by quantitative and qualitative alterations of extracellular matrix (ECM) proteins, is a critical cause of ventricular stiffness as well as impairment of left ventricular (LV) diastolic functions[1,2]
We show that a microtubule-associated RhoGEF, guanine nucleotide exchange factor (GEF)-H1, plays a key role in maladaptive fibrosis induced by mechanical stress and transforming growth factor (TGF)-βstimulation
Transverse aortic constriction (TAC) significantly increased myocardial cell size in both transient receptor potential canonical 3 (TRPC3)(+/+) and TRPC3(−/−) mice (Fig. 1a), collagen deposition determined by picrosirius red staining demonstrated a marked decrease of fibrosis in TRPC3(−/−) mouse hearts compared to TRPC3(+/+) (Fig. 1b)
Summary
Cardiac fibrosis, characterized by quantitative and qualitative alterations of extracellular matrix (ECM) proteins, is a critical cause of ventricular stiffness as well as impairment of left ventricular (LV) diastolic functions[1,2]. Mechanical stress is regarded as the initial stimulus for cardiac remodeling, and several mechano-sensitive or mechano-activated machineries have been suggested to translate changes in physical forces into intracellular signals, including ion channels, sarcomeric proteins, and integrins[5,6,7]. In addition to these direct sensors of stretch, locally or systemically released humoral factors, such as growth factors and agonists of G protein-coupled receptors, have been implicated in the hypertrophic responses. We show that a microtubule-associated RhoGEF, GEF-H1, plays a key role in maladaptive fibrosis induced by mechanical stress and TGF-βstimulation
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