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Sex hormones ameliorated sodium channel dysfunction induced by β-adrenergic overstimulation: the role of estrogen and G protein-coupled estrogen receptor

Background and Purpose: Sex hormones affect heart rhythm by regulating ion channels, but the effect of estrogen on cardiac voltage-gated sodium channel in stress-induced pathological conditions is currently not well defined. In this study, we explored the impact of various concentrations of estrogen and the role of its rapid receptor G protein-coupled estrogen receptor (GPER) on sodium channel function in a simulated cardiac stress model of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). Experimental Approach: Isoproterenol treated hiPSC-CMs were pre-incubated with various concentrations of β-Estradiol. Their sodium channel electrophysiological function and action potential were dissected by patch clamp and the content of sodium channel was observed by immunohistochemical method combined with laser scanning confocal microscopy. The GPER-specific effect was determined with agonists G1, antagonists G15 and small interfering RNA and sodium channel electrophysiology was selectively detected. Key Results: Isoproterenol-induced stress increased peak sodium current and late sodium current, and shortened action potential duration but the effects of stress were eliminated by β-Estradiol. Pearson Correlation analysis demonstrated no association between estrogenic effects on sodium currents versus content of sodium channel. Activation of GPER produced similar effects as β-Estradiol, while inhibition of GPER cancelled the effects induced by β-Estradiol. Conclusion and Implications: Estrogen through its rapid signal receptor GPER ameliorated the detrimental effects of β-adrenergic overstimulation like in cardiac stress on sodium channel dysfunction in hiPSC-CMs. These results are of great clinical significance as we need to understand the role of sex hormones in cardiovascular disease.