摘要：SummaryHigher risk of cardiac arrhythmias including atrial fibrillation (AF) associates with type 2 diabetes mellitus (T2DM) with the underlying mechanism largely unknown. The present study reported a subset of circulating immunoglobulin G autoantibodies (IgGs) from patients with T2DM with AF (T2DM/AF)-induced intracellular calcium elevation in both human induced pluripotent stem cell (iPSC)-derived and mouse atrial cardiomyocytes, whereas (identical concentrations of) IgGs from patients with T2DM without AF could not. The IgG-evoked intracellular calcium elevation was insensitive to verapamil, mibefradil, or BTP-2, indicating calcium source from neither voltage-gated calcium channels nor store-operated calcium entry. On the other hand, pharmacological antagonism or genetic knockdown of inositol triphosphate (IP3) receptor significantly decreased T2DM/AF IgG-induced intracellular calcium elevation. Furthermore, pharmacological blockage of G protein-coupled receptor (GPCR), heterotrimeric G protein or phospholipase C dampened IgG-induced intracellular calcium elevation. Taken together, circulating IgGs from patients with T2DM/AF stimulated arrhythmogenic intracellular calcium elevation through IP3pathway in atrial cardiomyocytes.Graphical AbstractDisplay OmittedHighlights•Identification of cardiomyocyte-targeting IgGs in T2DM atrial fibrillation patients•Induction of arrhythmogenic Ca2+signaling by these IgGs•Independent of voltage-gated or store-operated Ca2+channels•Involvement of GPCR-IP3-IP3R axis in IgG-evoked intracellular Ca2+elevationBiological Sciences; Physiology; Pathophysiology; Cellular Physiology
