iScience
Volume 23, Issue 4, 24 April 2020, 101036
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Article
Circulating IgGs in Type 2 Diabetes with Atrial Fibrillation Induce IP3-Mediated Calcium Elevation in Cardiomyocytes

https://doi.org/10.1016/j.isci.2020.101036Get rights and content
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Highlights

  • 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+ elevation

Summary

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.

Subject Areas

Biological Sciences
Physiology
Pathophysiology
Cellular Physiology

Cited by (0)

8

These authors contributed equally

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