MiRNA-1/133a Clusters Regulate Adrenergic Control of Cardiac Repolarization

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Abstract

The electrical properties of the heart are primarily determined by the activity of ion channels and the activity of these molecules is permanently modulated and adjusted to the physiological needs by adrenergic signaling. miRNAs are known to control the expression of many proteins and to fulfill distinct functions in the mammalian heart, though the in vivo effects of miRNAs on the electrical activity of the heart are poorly characterized. The miRNAs miR-1 and miR-133a are the most abundant miRNAs of the heart and are expressed from two miR-1/133a genomic clusters. Genetic modulation of miR-1/133a cluster expression without concomitant severe disturbance of general cardiomyocyte physiology revealed that these miRNA clusters govern cardiac muscle repolarization. Reduction of miR-1/133a dosage induced a longQT phenotype in mice especially at low heart rates. Longer action potentials in cardiomyocytes are caused by modulation of the impact of β-adrenergic signaling on the activity of the depolarizing L-type calcium channel. Pharmacological intervention to attenuate β-adrenergic signaling or L-type calcium channel activity in vivo abrogated the longQT phenotype that is caused by modulation of miR-1/133a activity. Thus, we identify the miR-1/133a miRNA clusters to be important to prevent a longQT-phenotype in the mammalian heart.

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Dysregulation of cardiogenesis, cardiac conduction, and cell cycle in mice lacking miRNA-1-2.

Yong Zhao, Joshua F Ransom, Ankang Li … (2007)

MicroRNAs (miRNAs) are genomically encoded small RNAs used by organisms to regulate the expression of proteins generated from messenger RNA transcripts. The in vivo requirement of specific miRNAs in mammals through targeted deletion remains unknown, and reliable prediction of mRNA targets is still problematic. Here, we show that miRNA biogenesis in the mouse heart is essential for cardiogenesis. Furthermore, targeted deletion of the muscle-specific miRNA, miR-1-2, revealed numerous functions in the heart, including regulation of cardiac morphogenesis, electrical conduction, and cell-cycle control. Analyses of miR-1 complementary sequences in mRNAs upregulated upon miR-1-2 deletion revealed an enrichment of miR-1 "seed matches" and a strong tendency for potential miR-1 binding sites to be located in physically accessible regions. These findings indicate that subtle alteration of miRNA dosage can have profound consequences in mammals and demonstrate the utility of mammalian loss-of-function models in revealing physiologic miRNA targets.

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The genetic basis of long QT and short QT syndromes: a mutation update.

Paula Hedley, Poul Jørgensen, Sarah Schlamowitz … (2009)

Long QT and short QT syndromes (LQTS and SQTS) are cardiac repolarization abnormalities that are characterized by length perturbations of the QT interval as measured on electrocardiogram (ECG). Prolonged QT interval and a propensity for ventricular tachycardia of the torsades de pointes (TdP) type are characteristic of LQTS, while SQTS is characterized by shortened QT interval with tall peaked T-waves and a propensity for atrial fibrillation. Both syndromes represent a high risk for syncope and sudden death. LQTS exists as a congenital genetic disease (cLQTS) with more than 700 mutations described in 12 genes (LQT1-12), but can also be acquired (aLQTS). The genetic forms of LQTS include Romano-Ward syndrome (RWS), which is characterized by isolated LQTS and an autosomal dominant pattern of inheritance, and syndromes with LQTS in association with other conditions. The latter includes Jervell and Lange-Nielsen syndrome (JLNS), Andersen syndrome (AS), and Timothy syndrome (TS). The genetics are further complicated by the occurrence of double and triple heterozygotes in LQTS and a considerable number of nonpathogenic rare polymorphisms in the involved genes. SQTS is a very rare condition, caused by mutations in five genes (SQTS1-5). The present mutation update is a comprehensive description of all known LQTS- and SQTS-associated mutations.

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L-type CaV1.2 calcium channels: from in vitro findings to in vivo function.

Jörg Wegener, Veit Flockerzi, Franz Hofmann … (2013)

The L-type Cav1.2 calcium channel is present throughout the animal kingdom and is essential for some aspects of CNS function, cardiac and smooth muscle contractility, neuroendocrine regulation, and multiple other processes. The L-type CaV1.2 channel is built by up to four subunits; all subunits exist in various splice variants that potentially affect the biophysical and biological functions of the channel. Many of the CaV1.2 channel properties have been analyzed in heterologous expression systems including regulation of the L-type CaV1.2 channel by Ca(2+) itself and protein kinases. However, targeted mutations of the calcium channel genes confirmed only some of these in vitro findings. Substitution of the respective serines by alanine showed that β-adrenergic upregulation of the cardiac CaV1.2 channel did not depend on the phosphorylation of the in vitro specified amino acids. Moreover, well-established in vitro phosphorylation sites of the CaVβ2 subunit of the cardiac L-type CaV1.2 channel were found to be irrelevant for the in vivo regulation of the channel. However, the molecular basis of some kinetic properties, such as Ca(2+)-dependent inactivation and facilitation, has been approved by in vivo mutagenesis of the CaV1.2α1 gene. This article summarizes recent findings on the in vivo relevance of well-established in vitro results.

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Author and article information

Contributors

Junming Yue: Role: Editor

Journal

Journal ID (nlm-ta): PLoS One

Journal ID (iso-abbrev): PLoS ONE

Journal ID (publisher-id): plos

Journal ID (pmc): plosone

Title: PLoS ONE

Publisher: Public Library of Science (San Francisco, USA )

ISSN (Electronic): 1932-6203

Publication date Collection: 2014

Publication date (Electronic): 21 November 2014

Volume: 9

Issue: 11

Electronic Location Identifier: e113449

Affiliations

[1 ]Department of Cardiac Development and Remodeling, Max-Planck-Institute for Heart and Lung Research, Bad Nauheim, Germany

[2 ]Institut für Physiologie I, Life & Brain Center, Universität Bonn, Bonn, Germany

The University of Tennessee Health Science Center, United States of America

Author notes

* E-mail: thomas.boettger@ 123456mpi-bn.mpg.de (TB); thomas.braun@ 123456mpi-bn.mpg.de (TB)

Competing Interests: The authors have declared that no competing interests exist.

Conceived and designed the experiments: JB PS BKF T. Braun T. Boettger. Performed the experiments: JB DM KW AB AW PS T. Boettger. Analyzed the data: JB DM KW AB PS T. Boettger. Wrote the paper: JB PS BKF T. Braun T. Boettger.

Article

Publisher ID: PONE-D-14-30695

DOI: 10.1371/journal.pone.0113449

PMC ID: 4240597

PubMed ID: 25415383

SO-VID: 3af7f9b6-bee9-488f-8584-3d4a91a9e1af

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This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

History

Date received : 10 July 2014

Date accepted : 24 October 2014

Page count

Pages: 18

Funding

The work was supported by the Max-Planck-Society ( www.mpg.de) and the Excellence Cluster Cardiopulmonary System ( www.eccps.de). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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Data Availability The authors confirm that all data underlying the findings are fully available without restriction. All relevant data are within the paper and its Supporting Information files. Microarray data are deposited at http://www.ebi.ac.uk/arrayexpress (Acc#E-MTAB-2727).

MiRNA-1/133a Clusters Regulate Adrenergic Control of Cardiac Repolarization

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Most cited references 29

Dysregulation of cardiogenesis, cardiac conduction, and cell cycle in mice lacking miRNA-1-2.

The genetic basis of long QT and short QT syndromes: a mutation update.

L-type CaV1.2 calcium channels: from in vitro findings to in vivo function.

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