Gal-3 (Galectin-3) and K3.1 Mediate Heterogeneous Cell Coupling and Myocardial Fibrogenesis Driven by βAR (β-Adrenoceptor) Activation.Ca

Gang She; Meng-Chen Hou; Yu Zhang; Yi Zhang; Yan Wang; Hui-Fang Wang; Bao-Chang Lai; Wei-Bo Zhao; Xiao-Jun Du; Xiu-Ling Deng
Abstract
Heart failure is associated with sympatho-βAR (β-adrenoceptor) activation and cardiac fibrosis. Gal-3 (galectin-3) and K3.1 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 K3.1 leading to cardiac fibrosis in the setting of βAR activation. We tested the effect of K3.1 blocker TRAM-34 on cardiac fibrosis and inflammation in cardiac-restricted β2-TG (β2AR overexpressed transgenic) mice and determined K3.1 expression in β-TG×Gal-3 mouse hearts. Mechanisms of K3.1 in mediating Gal-3 induced fibroblast activation were studied ex vivo. Expression of Gal-3 and K3.1 was elevated in β-TG hearts. gene deletion in β-TG mice decreased K3.1 expression in inflammatory cells but not in fibroblasts. Treatment of β-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 K3.1 expression and channel currents with enhanced membrane potential and Ca entry through TRPV4 (transient receptor potential V4) and TRPC6 (transient receptor potential C6) channels leading to fibroblast activation. In conclusion, βAR stimulation promotes Gal-3 production that upregulates K3.1 channels in noncardiomyocyte cells and activates K3.1 channels in fibroblasts leading to hyperpolarization of membrane potential and Ca entry via TRP channels. Gal-3-K3.1 signaling mobilizes diverse cells facilitating regional inflammation and fibroblast activation and hence myocardial fibrosis.Ca
Journal HYPERTENSION (DALLAS, TEX. : 1979)
ISSN 1524-4563
Published 16 Dec 2019
Volume
Issue
Pages HYPERTENSIONAHA11913696
DOI 10.1161/HYPERTENSIONAHA.119.13696
Type Journal Article
Sponsorship