Supplemental Digital Content is available in the text. Heart failure is associated with sympatho-βAR (β-adrenoceptor) activation and cardiac fibrosis. Gal-3 (galectin-3) and KCa3.1 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 KCa3.1 leading to cardiac fibrosis in the setting of βAR activation. We tested the effect of KCa3.1 blocker TRAM-34 on cardiac fibrosis and inflammation in cardiac-restricted β2-TG (β2AR overexpressed transgenic) mice and determined KCa3.1 expression in β2-TG×Gal-3−/− mouse hearts. Mechanisms of KCa3.1 in mediating Gal-3 induced fibroblast activation were studied ex vivo. Expression of Gal-3 and KCa3.1 was elevated in β2-TG hearts. Gal-3 gene deletion in β2-TG mice decreased KCa3.1 expression in inflammatory cells but not in fibroblasts. Treatment of β2-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 KCa3.1 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, βAR stimulation promotes Gal-3 production that upregulates KCa3.1 channels in noncardiomyocyte cells and activates KCa3.1 channels in fibroblasts leading to hyperpolarization of membrane potential and Ca2+ entry via TRP channels. Gal-3–KCa3.1 signaling mobilizes diverse cells facilitating regional inflammation and fibroblast activation and hence myocardial fibrosis.

中文翻译：

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Gal-3 (Galectin-3) 和 K Ca 3.1 介导由 βAR（β-肾上腺素能受体）激活驱动的异质细胞偶联和心肌纤维生成

补充数字内容在文本中可用。心力衰竭与交感神经-βAR（β-肾上腺素能受体）激活和心脏纤维化有关。在患病心脏的不同细胞中上调的 Gal-3（半乳糖凝集素 3）和 KCa3.1 通道与介导心肌炎症和纤维化有关。在 βAR 激活的情况下，Gal-3 是否与 KCa3.1 相互作用导致心脏纤维化尚不清楚。我们测试了 KCa3.1 阻滞剂 TRAM-34 对心脏受限的 β2-TG（β2AR 过表达转基因）小鼠心脏纤维化和炎症的影响，并确定了 β2-TG×Gal-3-/- 小鼠心脏中的 KCa3.1 表达。离体研究了 KCa3.1 在介导 Gal-3 诱导的成纤维细胞活化中的机制。Gal-3 和 KCa3.1 在 β2-TG 心脏中的表达升高。β2-TG 小鼠中的 Gal-3 基因缺失降低了 KCa3。1 在炎症细胞中表达，但在成纤维细胞中不表达。用 TRAM-34 治疗 β2-TG 小鼠 1 或 2 个月可显着改善心脏炎症和纤维化并降低 Gal-3 水平。在培养的成纤维细胞中，Gal-3 上调 KCa3.1 表达和通道电流，增强膜电位和 Ca2+ 通过 TRPV4（瞬时受体电位 V4）和 TRPC6（瞬时受体电位 C6）通道进入，导致成纤维细胞活化。总之，βAR 刺激促进 Gal-3 产生，上调非心肌细胞中的 KCa3.1 通道并激活成纤维细胞中的 KCa3.1 通道，导致膜电位超极化和 Ca2+ 通过 TRP 通道进入。Gal-3-KCa3.1 信号调动多种细胞，促进局部炎症和成纤维细胞活化，从而促进心肌纤维化。