Tachy-paced cardiomyocyte-derived small extracellular vesicles impair SERCA2a-dependent Ca2+ handling in recipient cardiomyocytes

Background

Sustained tachyarrhythmia is a major cause of cardiac dysfunction and can lead to tachycardia-induced cardiomyopathy (TIC). However, the role of small extracellular vesicle (sEV)-mediated intercellular communication in the pathogenesis of TIC remains poorly understood. We aimed to investigate whether sEVs derived from tachy-paced cardiomyocytes affect intracellular Ca2+ handling in recipient cardiomyocytes. Methods and results: Cultured murine atrial cardiomyocytes (HL-1 cells) were subjected to high-frequency electrical stimulation (tachy-pacing, 10 Hz), and sEVs were isolated from the culture supernatant. sEVs derived from the tachy-paced cells and non-paced control cells were subsequently applied to neonatal mouse cardiomyocytes (NMCMs). Intracellular Ca2+ transients, sarcoplasmic reticulum (SR) Ca2+ content, and the expression of Ca2+-handling proteins were evaluated. High-frequency electrical stimulation significantly increased sEV secretion from HL-1 cells. sEVs derived from tachy-paced HL-1 cells markedly slowed Ca2+ decay and reduced SERCA2a protein expression in recipient NMCMs.