Gal-3 (Galectin-3) and KCa3.1 Mediate Heterogeneous Cell Coupling and Myocardial Fibrogenesis Driven by βAR (β-Adrenoceptor) Activation

Heart failure is associated with sympatho-beta AR (beta-adrenoceptor) activation and cardiac fibrosis. Gal-3 (galectin-3) and K(Ca)3.1 channels that are upregulated in diverse cells of diseased heart are implicated in mediating myocardial inflammation and fibrosis. It remains unclear whether Gal-3 interacts with K(Ca)3.1 leading to cardiac fibrosis in the setting of beta AR activation. We tested the effect of K(Ca)3.1 blocker TRAM-34 on cardiac fibrosis and inflammation in cardiac-restricted beta(2)-TG (beta(2)AR overexpressed transgenic) mice and determined K(Ca)3.1 expression in beta(2)-TGxGal-3(-/-) mouse hearts. Mechanisms of K(Ca)3.1 in mediating Gal-3 induced fibroblast activation were studied ex vivo. Expression of Gal-3 and K(Ca)3.1 was elevated in beta(2)-TG hearts. Gal-3 gene deletion in beta(2)-TG mice decreased K(Ca)3.1 expression in inflammatory cells but not in fibroblasts. Treatment of beta(2)-TG mice with TRAM-34 for 1 or 2 months significantly ameliorated cardiac inflammation and fibrosis and reduced Gal-3 level. In cultured fibroblasts, Gal-3 upregulated K(Ca)3.1 expression and channel currents with enhanced membrane potential and Ca2+ entry through TRPV4 (transient receptor potential V4) and TRPC6 (transient receptor potential C6) channels leading to fibroblast activation. In conclusion, beta AR stimulation promotes Gal-3 production that upregulates K(Ca)3.1 channels in noncardiomyocyte cells and activates K(Ca)3.1 channels in fibroblasts leading to hyperpolarization of membrane potential and Ca2+ entry via TRP channels. Gal-3-K(Ca)3.1 signaling mobilizes diverse cells facilitating regional inflammation and fibroblast activation and hence myocardial fibrosis.