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      Identification of Key Small Non‐Coding MicroRNAs Controlling Pacemaker Mechanisms in the Human Sinus Node

      , PhD 1 , , PhD 1 , , PhD 1 , , MRes 1 , , MRes 1 , , MSc 6 , , PhD 6 , , MBChB 1 , , MRes 1 , , PhD 2 , , PhD 1 , , PhD 1 , , PhD 3 , , PhD 4 , 5 , , PhD 1 , , PhD 2 , , PhD , 1 , 7

      Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease

      John Wiley and Sons Inc.

      ion channels, microRNAs, pacemaker of the heart, sinus node disease, Basic Science Research, Translational Studies, Mechanisms, Ion Channels/Membrane Transport, Gene Therapy

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          Abstract

          Background

          The sinus node (SN) is the primary pacemaker of the heart. SN myocytes possess distinctive action potential morphology with spontaneous diastolic depolarization because of a unique expression of ion channels and Ca 2+‐handling proteins. MicroRNAs (miRs) inhibit gene expression. The role of miRs in controlling the expression of genes responsible for human SN pacemaking and conduction has not been explored. The aim of this study was to determine miR expression profile of the human SN as compared with that of non‐pacemaker atrial muscle.

          Methods and Results

          SN and atrial muscle biopsies were obtained from donor or post‐mortem hearts (n=10), histology/immunolabeling were used to characterize the tissues, TaqMan Human MicroRNA Arrays were used to measure 754 miRs, Ingenuity Pathway Analysis was used to identify miRs controlling SN pacemaker gene expression. Eighteen miRs were significantly more and 48 significantly less abundant in the SN than atrial muscle. The most interesting miR was miR‐486‐3p predicted to inhibit expression of pacemaking channels: HCN1 (hyperpolarization‐activated cyclic nucleotide‐gated 1), HCN4, voltage‐gated calcium channel (Ca v)1.3, and Ca v3.1. A luciferase reporter gene assay confirmed that miR‐486‐3p can control HCN4 expression via its 3′ untranslated region. In ex vivo SN preparations, transfection with miR‐486‐3p reduced the beating rate by ≈35±5% ( P<0.05) and HCN4 expression ( P<0.05).

          Conclusions

          The human SN possesses a unique pattern of expression of miRs predicted to target functionally important genes. miR‐486‐3p has an important role in SN pacemaker activity by targeting HCN4, making it a potential target for therapeutic treatment of SN disease such as sinus tachycardia.

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          Most cited references 20

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          Mechanisms of post-transcriptional regulation by microRNAs: are the answers in sight?

          MicroRNAs constitute a large family of small, approximately 21-nucleotide-long, non-coding RNAs that have emerged as key post-transcriptional regulators of gene expression in metazoans and plants. In mammals, microRNAs are predicted to control the activity of approximately 30% of all protein-coding genes, and have been shown to participate in the regulation of almost every cellular process investigated so far. By base pairing to mRNAs, microRNAs mediate translational repression or mRNA degradation. This Review summarizes the current understanding of the mechanistic aspects of microRNA-induced repression of translation and discusses some of the controversies regarding different modes of microRNA function.
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            MicroRNAs in cardiovascular disease: an introduction for clinicians

            MicroRNAs (miRNAs) are small, non-coding, RNA molecules approximately 22 nucleotides in length which act as post-transcriptional regulators of gene expression. Individual miRNAs have been shown to regulate the expression of multiple genes. Conversely, the expression of individual genes can be regulated by multiple miRNAs. Consequently, since their discovery just over 20 years ago, miRNAs have been identified as key regulators of complex biological processes linked to multiple cardiovascular pathologies, including left ventricular hypertrophy, ischaemic heart disease, heart failure, hypertension and arrhythmias. Furthermore, since the finding that miRNAs are present in the circulation, they have been investigated as novel biomarkers, especially in the context of acute myocardial infarction (AMI) and heart failure. While there is little convincing evidence that miRNAs can outperform traditional biomarkers, such as cardiac troponins, in the diagnosis of AMI, there is potential for miRNAs to complement existing risk prediction models and act as valuable markers of post-AMI prognosis. Encouragingly, the concept of miRNA-based therapeutics is developing, with synthetic antagonists of miRNAs (antagomiRs) currently in phase II trials for the treatment of chronic hepatitis C virus infection. In the cardiovascular field, promising preclinical studies suggest that they could be useful in treating disorders ranging from heart failure to dyslipidaemia, although several challenges related to specificity and targeted delivery remain to be overcome. Through this review, we provide clinicians with a brief overview of the ever-expanding world of miRNAs.
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              miRBase: microRNA sequences, targets and gene nomenclature

              The miRBase database aims to provide integrated interfaces to comprehensive microRNA sequence data, annotation and predicted gene targets. miRBase takes over functionality from the microRNA Registry and fulfils three main roles: the miRBase Registry acts as an independent arbiter of microRNA gene nomenclature, assigning names prior to publication of novel miRNA sequences. miRBase Sequences is the primary online repository for miRNA sequence data and annotation. miRBase Targets is a comprehensive new database of predicted miRNA target genes. miRBase is available at .
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                Author and article information

                Contributors
                halina.dobrzynski@manchester.ac.uk
                Journal
                J Am Heart Assoc
                J Am Heart Assoc
                10.1002/(ISSN)2047-9980
                JAH3
                ahaoa
                Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease
                John Wiley and Sons Inc. (Hoboken )
                2047-9980
                16 October 2020
                20 October 2020
                : 9
                : 20 ( doiID: 10.1002/jah3.v9.20 )
                Affiliations
                [ 1 ] Division of Cardiovascular Sciences University of Manchester United Kingdom
                [ 2 ] Physiology and Cell Biology Department The Bob and Corrine Frick Center for Heart Failure and Arrhythmia The Ohio State University Wexner Medical Center Columbus OH
                [ 3 ] National Institute of Legal Medicine Bucharest Romania
                [ 4 ] School of Biomedical Sciences Queensland University of Technology Brisbane Australia
                [ 5 ] Cardiovascular Molecular & Therapeutics Translational Research Group The Prince Charles Hospital Brisbane Australia
                [ 6 ] Department of Human and Animal Physiology Lomonosov Moscow State University Moscow Russia
                [ 7 ] Department of Anatomy Jagiellonian University Medical College Krakow Poland
                Author notes
                [* ] Correspondence to: Halina Dobrzynski, PhD, University of Manchester, CTF building, 46 Grafton Street, Manchester M13 9NT, United Kingdom. E‐mail: halina.dobrzynski@ 123456manchester.ac.uk

                [*]

                Dr Petkova and Mr Atkinson are co‐first authors.

                [†]

                Dr Fedorov and Dr Dobrzynski are co‐last authors.

                Article
                JAH35599
                10.1161/JAHA.120.016590
                7763385
                33059532
                © 2020 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.

                This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

                Page count
                Figures: 7, Tables: 1, Pages: 15, Words: 8121
                Product
                Funding
                Funded by: Leducq Foundation , open-funder-registry 10.13039/501100001674;
                Award ID: 19CVD03
                Funded by: British Heart Foundation , open-funder-registry 10.13039/501100000274;
                Award ID: RG/18/2/33392
                Funded by: NIH , open-funder-registry 10.13039/100000002;
                Award ID: HL115580
                Award ID: HL135109
                Funded by: Russian Science Foundation , open-funder-registry 10.13039/501100006769;
                Award ID: 19‐15‐00163
                Categories
                Original Research
                Original Research
                Molecular Cardiology
                Custom metadata
                2.0
                20 October 2020
                Converter:WILEY_ML3GV2_TO_JATSPMC version:5.9.4 mode:remove_FC converted:20.11.2020

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