MicroRNA-365 regulates human cardiac action potential duration

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.

MikroRNA w zaburzeniach rytmu serca

“…In cardiomyocytes from short-QT syndrome patients, an important level of miR-365 was able to normalize QT time, whereas inhibition of miR-365 normalized prolonged QT in long-QT syndrome cells. The study confirmed miR-365-dependent regulation of repolarizing ionic potassium current [31].…”

MicroRNAs as therapeutic targets in cardiovascular disease

“…Tissue explants are another system with a human genetic background. Cardiac slices or aortic tissue from human patients maintain their organotypical features in culture ( 50 , 51 ) and can be manipulated by viral transduction ( 52 , 53 ), transfection ( 54 ), or used in coculture experiments ( 55 , 56 ).…”

“…On the other hand, an individual microRNA may also regulate various levels of a cellular process. Examples of such multilevel regulation include miR-378a-3p, the miR-29 family, and miR-365-3p ( 54 , 74 , 75 ). In conclusion, activities in concert or on several layers add to the power of microRNAs as disease modifiers.…”

Advances in Single-Cell Multi-Omics and Application in Cardiovascular Research

“…They also developed a cell fate index (CFI) algorithm to assess reprogramming progression and provide valuable insights into how to optimize the differentiation methods ( Zhou et al, 2019 ). Based on hPSC-derived CMs, scRNA-seq was also used to measure the gene regulatory network in drug screening ( Ballan et al, 2020 ), cellular processes under physiological ( Cyganek et al, 2018 ; Gambardella et al, 2019 ; Schmid et al, 2021 ; Esfandyari et al, 2022 ) and pathological conditions ( Guo et al, 2019 ) ( Kathiriya et al, 2021 ) and developmental progression ( Hulin et al, 2019 ; Ruan et al, 2019 ; Sahara et al, 2019 ).…”