The mechanism of G protein-mediated cardiac fibrosis

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Sustained elevation of intracellular Ca^2+ concentration ([Ca^2+]i) has been implicated in many cellular events. We reported that sustained Ca^2+ influx through canonical transient receptor potential 3/6 (TRPC3/6) channels pathway leads to the activation of nuclear factor of activated T cells (NFAT), a Ca^2+-responsive transcriptional factor, and meditates hypertrophic responses in rat neonatal cardiac myocytes. We also demonstrated that TRPC6 channels participates in sustained Ca^2+ influx and NFAT activation by endothelin (ET)-1 treatment in cardiac fibroblasts. Expression of constitutively active (CA) G_α<12> or G_α<13> increased the expression of TRPC6 proteins and basal Ca^2+ influx activity. The treatment with ET-1 increased TRPC6 protein levels through G_α<12/13>, reactive oxygen species (ROS), and c-Jun N-terminal kinase (JNK)-dependent pathways. NFAT is activated by sustained increase in [Ca^2+]; through upregulated TRPC6. A G_α<12/13>-inhibitory polypeptide derived from regulator of G-protein signaling domain of p115-RhoGEF and a JNK inhibitor, SP600125, suppressed the ET-1-induced increase in expression of marker proteins of myofibroblast formation through G_α<12/13>-ROS-JNK pathway. The ET-1-induced myofibroblast formation was suppressed by overexpression of TRPC6 and CA-NFAT, while enhanced by TRPC6 siRNAs and cyclosporine A. These results suggest two opposite roles of G_α<12/13> in cardiac fibroblasts. First, G_α<12/13> mediate ET-1-induced myofibroblast formation. Second, G_α<12/13> mediate TRPC6 upregulation and NFAT activation that negatively regulates ET-1-induced myofibroblast formation. Furthermore, TRPC6 mediates hypertrophic responses in cardiac myocytes but suppresses fibrotic responses in cardiac fibroblasts. Thus, TRPC6 mediates opposite responses in cardiac myocytes and fibroblasts.