FGF23 regulates atrial fibrosis in atrial fibrillation by mediating the STAT3 and SMAD3 pathways

High fibroblast growth factor 23 (FGF23) concentrations are a strong predictor of atrial fibrillation (AF), but researchers have not clearly determined the mechanism by which FGF23 causes atrial fibrosis in patients with AF. This study aims to elucidate the mechanism by which FGF23 induces atrial fibrosis in patients with AF. Immunohistochemistry was used to study the expression of FGF23, FGFR4, and fibrotic factors in patients with a normal sinus rhythm (SR) and patients with AF. Cardiac fibroblasts (CFs) were cocultured with different concentrations of the recombinant FGF23 protein. Compared with the SR group, the levels of FGF23, FGFR4, alpha-smooth muscle actin (alpha-SMA), and collagen-1 were significantly increased in the AF group. Exposure to high concentrations of the recombinant FGF23 protein increased the accumulation of reactive oxygen species (ROS) and activated alpha-SMA, collagen-1, signal transducer and activator of transcription 3 (STAT3) and SMAD3 signaling in cultured CFs. The levels of fibrotic proteins in CFs stimulated with high concentrations of the recombinant FGF23 protein were reversed by N-acetylcysteine (NAC, a ROS inhibitor), ship information system 3 (a SMAD3 inhibitor), and Stattic (a STAT3 inhibitor). Furthermore, compared to untreated CFs, CFs treated with the recombinant FGF23 protein were characterized by an increased interaction between STAT3 and SMAD3. Based on these results, FGF23 induces atrial fibrosis in patients with AF by increasing ROS production and subsequently activating STAT3 and SMAD3 signaling.