Non-coding RNAs in cardiac arrhythmia
patient-specific induced pluripotent stem cell-derived cardiac myocytes (hiPSC-CMs), Day30 after differentiation
Team: Dena Esfandyari, Gheo Idrissou, Andrea Welling, Urszula Kremser, Sabine Brummer, Anton Bomhard, Julia Auerswald, Alora Marks
Ventricular arrhythmias contribute to 75–80% of cases of sudden cardiac death, a major cause of death in developed nations. New therapeutic interventions for such cardiac arrhythmia are urgently needed since current pharmacological treatments have met considerable challenges. MicroRNAs hold high promise as targets for new cardiovascular therapies, with substantial progress made in recent years (1), and lncRNAs are expected to follow along this line.
Our research focuses on the identification and characterization of non-coding RNAs (e.g., microRNAs and long non-coding RNAs) that regulate cardiac rhythm-related genes (2, 3), with the ultimate goal of leveraging their potential as therapeutic modulators of human cardiac arrhythmias.
Over the past few years, we developed a multidisciplinary toolbox to tackle this research question:
For disease modeling, we use patient-specific induced pluripotent stem cell-derived cardiac myocytes (hiPSC-CMs), precision-cut slices from the human heart, and various mouse strains. In these models, we manipulate the level of candidate non-coding RNAs using adeno-associated viruses (AAVs) and CRISPR-based approaches. Utilizing various measurement techniques, including FRET microscopy, multielectrode arrays (MEA), and electrocardiography (ECG), we determine the action potential abnormalities. We employ state-of-the-art transcriptomics, including single cell RNA-seq, to decipher the molecular mechanisms underlying non-coding RNA control of cardiac rhythm.
Using this methodology, we have characterized miR-365 as a primary microRNA that regulates repolarizing ion channels and ameliorates action potential abnormalities in hiPSC-CM models of QT syndrome. (2)
More recently, we have extended the scope of our analyzes to lncRNAs, based on evidence from our work and that of others (3) that this group of ncRNAs has a striong role in cardiac electrophysiology.
(1) Laggerbauer B, Engelhardt S. MicroRNAs as therapeutic targets in cardiovascular disease. J Clin Invest. 2022;132. doi:10.1172/JCI159179(link is external)
(2) Esfandyari D, Idrissou BMG, Hennis K, Avramopoulos P, Dueck A, El-Battrawy I, Grüter L, Meier MA, Näger AC, Ramanujam D, Dorn T, Meitinger T, Hagl C, Milting H, Borggrefe M, Fenske S, Biel M, Dendorfer A, Sassi Y, Moretti A, Engelhardt S. MicroRNA-365 regulates human cardiac action potential duration. Nat Commun. 2022;13:220. doi:10.1038/s41467-021-27856-7(link is external)
(3) Zhang Y, Du W, Yang B. Long non-coding RNAs as new regulators of cardiac electrophysiology and arrhythmias: Molecular mechanisms, therapeutic implications and challenges. Pharmacol Ther. 2019;203:107389. doi:10.1016/j.pharmthera.2019.06.011(link is external)