Elevated KCa3.1 expression by angiotensin II via the ERK/NF-κB pathway contributes to atrial fibrosis

Abstract

Atrial fibrillation (AF) is a prevalent cardiac arrhythmia characterized by atrial fibrosis which involves excessed proliferation and increased activity of fibroblast and myofibroblast, as well as alterations in the extracellular matrix (ECM). The specific mechanism driving fibrosis in atrial fibroblasts and myofibroblsats remains incompletely understood. This study investigates the role of the intermediate-conductance Ca²⁺-activated K⁺ channel (K_Ca3.1) in Angiotensin II (Ang II)-induced atrial fibrosis and elucidates the underlying mechanisms. Primary rat atrial fibroblasts/myofibroblasts were treated with Ang II to evaluate K_Ca3.1 expression, cells proliferation and ECM production. The involvement of ERK/NF-κB signaling pathway was assessed using specific inhibitors. Ang II treatment increased K_Ca3.1 expression, stimulated the proliferation of fibroblasts/myofibroblasts, and enhanced ECM production, effects that were attenuated by the Ang II receptor antagonist Losartan and the K_Ca3.1 inhibitor TRAM-34. Knockdown of K_Ca3.1 using siRNA significantly reduced Ang II-induced collagen synthesis, confirming its critical role in fibrosis. The ERK/NF-κB pathway was found to mediate Ang II-induced upregulation of K_Ca3.1, as evidenced by inhibition with specific inhibitors. In vivo, Ang II infusion in rats increased K_Ca3.1 expression and atrial fibrosis, with atria showing greater susceptibility to fibrosis compared to ventricle. These effects were mitigated by losartan and TRAM-34. In conclusion, our findings demonstrate that Ang II-induced upregulation of K_Ca3.1 through ERK/NF-κB pathway activation in atrial fibroblasts/myofibroblasts promotes cellular proliferation and collagen deposition, ultimately contributing to atrial fibrosis. K_Ca3.1 represents a promising therapeutic target for the treatment of atrial fibrosis in AF.