KCa3.1 promotes exosomes secretion by activating on AKT/Rab27a in atrial myocytes during rapid pacing

Abstract

Purpose the aim of this study was to investigate the role of intermediate-conductance Ca2+-activated K+ (KCNN4, KCa3.1) in exosomes secretion of atrial myocytes. Methods eighteen beagles were randomly divided into Sham group (n = 6), Pacing group (n = 6), and Pacing + TRAM-34 group (n = 6). The in vivo electrophysiological data such as effective refractory period, atrial fibrillation (AF) induction, and AF duration were collected by programmed stimulation. Atrial tissues were stained with Hematoxylin & Eosin and Masson’s trichrome. The expression of KCa3.1 and Rab27a were accessed by immunohistochemistry and western blot. The downstream signaling pathways involved in KCa3.1 were explored by rapid pacing and overexpressing KCNN4 in HL-1 cells. Results TRAM-34 (KCa3.1 blocker) significantly inhibits electrical remodeling, inflammation, fibrosis, and exosomes secretion in rapid atrial pacing canines. More importantly, the vitro experiments demonstrated that KCa3.1 regulates the exosomes secretion through AKT/Rab27a signaling pathways. The use of calcium chelator, AKT inhibitor and si-Rab27a also significantly inhibit the exosomes secretion. Moreover, exosomes derived from rapid pacing HL-1 cells promote M1 polarization. Conclusions This study found that KCa3.1 promotes pro-inflammatory exosome secretion through the AKT/Rab27a signaling pathway. Inhibition KCa3.1/AKT/Rab27a signal pathway reduces myocardial tissue structure remodeling in AF.