MicroRNA-365 regulates human cardiac action potential duration

Dena Esfandyari, Bio Maria Ghéo Idrissou, Konstantin Hennis, Petros Avramopoulos, Anne Dueck, Ibrahim El-Battrawy, Laurenz Grüter, Melanie Annemarie Meier, Anna Christina Näger, Deepak Ramanujam, Tatjana Dorn, Thomas Meitinger, Christian Hagl, Hendrik Milting, Martin Borggrefe, Stefanie Fenske, Martin Biel, Andreas Dendorfer, Yassine Sassi, Alessandra Moretti and Stefan Engelhardt ()
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Dena Esfandyari: Technical University of Munich (TUM)
Bio Maria Ghéo Idrissou: Technical University of Munich (TUM)
Konstantin Hennis: Center for Drug Research, Department of Pharmacy, Ludwig-Maximilians-Universität München
Petros Avramopoulos: Technical University of Munich (TUM)
Anne Dueck: Technical University of Munich (TUM)
Ibrahim El-Battrawy: DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance
Laurenz Grüter: Technical University of Munich (TUM)
Melanie Annemarie Meier: Technical University of Munich (TUM)
Anna Christina Näger: Technical University of Munich (TUM)
Deepak Ramanujam: Technical University of Munich (TUM)
Tatjana Dorn: Technical University of Munich (TUM)
Thomas Meitinger: DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance
Christian Hagl: University Hospital, Ludwig-Maximilians-Universität München
Hendrik Milting: University Hospital of the Ruhr-University Bochum
Martin Borggrefe: DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance
Stefanie Fenske: DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance
Martin Biel: Center for Drug Research, Department of Pharmacy, Ludwig-Maximilians-Universität München
Andreas Dendorfer: DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance
Yassine Sassi: Technical University of Munich (TUM)
Alessandra Moretti: DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance
Stefan Engelhardt: Technical University of Munich (TUM)

Nature Communications, 2022, vol. 13, issue 1, 1-15

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-021-27856-7

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