MicroRNA-365 regulates human cardiac action potential duration

Dena Esfandyari,Laurenz Grüter,Bio Maria Ghéo Idrissou,Anna Christina Näger,Hendrik Milting,Alessandra Moretti,Anne Dueck,Tatjana Dorn,Stefanie Fenske,Christian Hagl,Petros Avramopoulos,Deepak Ramanujam,Ibrahim El‐Battrawy ,Martin Biel,Yassine Sassi,Melanie Meier ,Konstantin Hennis,Thomas Meitinger,Andreas Dendorfer,Martin Borggrefe,Stefan Engelhardt

doi:10.1038/s41467-021-27856-7

Abstract

Abnormalities of ventricular action potential cause malignant cardiac arrhythmias and sudden cardiac death. Here, we aim to identify microRNAs that regulate the human cardiac action potential and ask whether their manipulation allows for therapeutic modulation of action potential abnormalities. Quantitative analysis of the microRNA targetomes in human cardiac myocytes identifies miR-365 as a primary microRNA to regulate repolarizing ion channels. Action potential recordings in patient-specific induced pluripotent stem cell-derived cardiac myocytes show that elevation of miR-365 significantly prolongs action potential duration in myocytes derived from a Short-QT syndrome patient, whereas specific inhibition of miR-365 normalizes pathologically prolonged action potential in Long-QT syndrome myocytes. Transcriptome analyses in these cells at bulk and single-cell level corroborate the key cardiac repolarizing channels as direct targets of miR-365, together with functionally synergistic regulation of additional action potential-regulating genes by this microRNA. Whole-cell patch-clamp experiments confirm miR-365-dependent regulation of repolarizing ionic current Iks. Finally, refractory period measurements in human myocardial slices substantiate the regulatory effect of miR-365 on action potential in adult human myocardial tissue. Our results delineate miR-365 to regulate human cardiac action potential duration by targeting key factors of cardiac repolarization.

Highlights

Abnormalities of ventricular action potential cause malignant cardiac arrhythmias and sudden cardiac death
To assess the human cardiac channelome in these data, we first extracted a list of 27 genes from the UniProt Knowledge-based database[13], which code for proteins that are confidently annotated and reviewed as ion channels involved in the repolarization phase of the action potential (AP)
Here we report on miR-365, a miRNA that is highly expressed in human cardiac myocytes and that we found to regulate cardiac repolarization

Summary

Introduction

Abnormalities of ventricular action potential cause malignant cardiac arrhythmias and sudden cardiac death. Action potential recordings in patient-specific induced pluripotent stem cell-derived cardiac myocytes show that elevation of miR-365 significantly prolongs action potential duration in myocytes derived from a Short-QT syndrome patient, whereas specific inhibition of miR-365 normalizes pathologically prolonged action potential in Long-QT syndrome myocytes Transcriptome analyses in these cells at bulk and single-cell level corroborate the key cardiac repolarizing channels as direct targets of miR-365, together with functionally synergistic regulation of additional action potential-regulating genes by this microRNA. Typically due to heterozygous mutations in ion channel genes, can shift the balance of currents toward prolongation of AP duration and QT interval, known as Long-QT syndrome (LQTS), while an increase of outward currents causes shortening of repolarization duration and shorter QT intervals (Short-QT syndrome, SQTS) Such ventricular arrhythmias may progress to ventricular fibrillation and sudden cardiac death (SCD)[3,4,5]. A regulatory role of distinct miRNAs has been reported for various aspects of cardiac rhythm control and arrhythmias[8]

Objectives

Methods

Results

Conclusion