Circulating IgGs in Type 2 Diabetes with Atrial Fibrillation Induce IP₃-Mediated Calcium Elevation in Cardiomyocytes.

ABSTRACT: Higher 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 IP₃ pathway in atrial cardiomyocytes.

SUBMITTER: Luo Y 

PROVIDER: S-EPMC7170991 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature