K3.1 upregulation mediated by Ang II-induced JNK/AP-1 activation contributes to atrial fibrosis.

Atrial fibrillation is strongly associated with an increased risk of embolism, stroke, and heart failure. Current therapeutic approaches often have limited efficacy, and controlling atrial fibrosis remains a critical objective for upstream therapies. The specific mechanisms driving atrial fibrosis remain incompletely understood. The intermediate-conductance calcium-activated potassium channel K3.1 has been implicated in promoting fibroblast activation in various fibrotic diseases. This study investigates the role of angiotensin II (Ang II) in regulating K3.1, as well as its involvement in the pathogenesis of atrial fibrosis and the underlying signaling mechanisms. In a rat model, chronic Ang II infusion for 4 weeks induced atrial fibrosis, which was significantly attenuated by TRAM-34, a specific K3.1 channel blocker. In cultured rat atrial fibroblasts, Ang II treatment promoted fibroblast differentiation, proliferation, migration and collagen production, effects that were suppressed by TRAM-34 and K3.1 knockdown. Overexpression of K3.1 in fibroblasts further confirmed its pro-fibrotic role. Mechanistically, Ang II upregulated K3.1 expression and current density by activating the JNK/AP-1 signaling pathway. This involved phosphorylation of JNK, c-Jun, and c-Fos, leading to the formation of c-Jun/c-Fos heterodimers that directly bound to the K3.1 promoter to enhance its transcription. Together, these findings demonstrate that K3.1 mediates fibroblast activation and atrial fibrosis through the JNK/AP-1 pathway.