MicroRNA-365 regulates human cardiac action potential duration

dc.contributor.authorEsfandyari, Denaen
dc.contributor.authorIdrissou, Bio Maria Ghéoen
dc.contributor.authorHennis, Konstantinen
dc.contributor.authorAvramopoulos, Petrosen
dc.contributor.authorDueck, Anneen
dc.contributor.authorEl-Battrawy, Ibrahimen
dc.contributor.authorGrüter, Laurenzen
dc.contributor.authorMeier, Melanie Annemarieen
dc.contributor.authorNäger, Anna Christinaen
dc.contributor.authorRamanujam, Deepaken
dc.contributor.authorDorn, Tatjanaen
dc.contributor.authorMeitinger, Thomasen
dc.contributor.authorHagl, Christianen
dc.contributor.authorMilting, Hendriken
dc.contributor.authorBorggrefe, Martinen
dc.contributor.authorFenske, Stefanieen
dc.contributor.authorBiel, Martinen
dc.contributor.authorDendorfer, Andreasen
dc.contributor.authorSassi, Yassineen
dc.contributor.authorMoretti, Alessandraen
dc.contributor.authorEngelhardt, Stefanen
dc.date.accessioned2022-01-14T16:20:31Zen
dc.date.available2022-01-14T16:20:31Zen
dc.date.issued2022-01-11en
dc.date.updated2022-01-14T16:20:29Zen
dc.description.abstractAbnormalities 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 I<jats:sub>ks</jats:sub>. 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.en
dc.description.versionPublished versionen
dc.format.extentPages 220en
dc.format.mimetypeapplication/pdfen
dc.identifier220 (Article number)en
dc.identifier.doihttps://doi.org/10.1038/s41467-021-27856-7en
dc.identifier.eissn2041-1723en
dc.identifier.issn2041-1723en
dc.identifier.issue1en
dc.identifier.orcidSassi, Yassine [0000-0002-7807-1728]en
dc.identifier.urihttp://hdl.handle.net/10919/107641en
dc.identifier.volume13en
dc.language.isoenen
dc.publisherSpringer Natureen
dc.rightsCreative Commons Attribution 4.0 Internationalen
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en
dc.titleMicroRNA-365 regulates human cardiac action potential durationen
dc.title.serialNature Communicationsen
dc.typeArticle - Refereeden
dc.type.dcmitypeTexten
pubs.organisational-group/Virginia Techen
pubs.organisational-group/Virginia Tech/University Research Institutesen
pubs.organisational-group/Virginia Tech/All T&R Facultyen

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