Identification of Key Small Non‐Coding MicroRNAs Controlling Pacemaker Mechanisms in the Human Sinus Node
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 Ca2+‐handling proteins. MicroRNAs (miRs) inhibit gene expression. The role of...
| Main Authors: | , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Wiley
2020-10-01
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| Series: | Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease |
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| Online Access: | https://www.ahajournals.org/doi/10.1161/JAHA.120.016590 |
| _version_ | 1818238906961756160 |
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| author | Maria Petkova Andrew J. Atkinson Joseph Yanni Luke Stuart Abimbola J. Aminu Alexandra D. Ivanova Ksenia B. Pustovit Connor Geragthy Amy Feather Ning Li Yu Zhang Delvac Oceandy Filip Perde Peter Molenaar Alicia D’Souza Vadim V. Fedorov Halina Dobrzynski |
| author_facet | Maria Petkova Andrew J. Atkinson Joseph Yanni Luke Stuart Abimbola J. Aminu Alexandra D. Ivanova Ksenia B. Pustovit Connor Geragthy Amy Feather Ning Li Yu Zhang Delvac Oceandy Filip Perde Peter Molenaar Alicia D’Souza Vadim V. Fedorov Halina Dobrzynski |
| author_sort | Maria Petkova |
| collection | DOAJ |
| description | 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 Ca2+‐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 (Cav)1.3, and Cav3.1. 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. |
| first_indexed | 2024-12-12T12:49:06Z |
| format | Article |
| id | doaj.art-375542e1a34747dcbe6c389f36654b67 |
| institution | Directory Open Access Journal |
| issn | 2047-9980 |
| language | English |
| last_indexed | 2024-12-12T12:49:06Z |
| publishDate | 2020-10-01 |
| publisher | Wiley |
| record_format | Article |
| series | Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease |
| spelling | doaj.art-375542e1a34747dcbe6c389f36654b672022-12-22T00:24:02ZengWileyJournal of the American Heart Association: Cardiovascular and Cerebrovascular Disease2047-99802020-10-0192010.1161/JAHA.120.016590Identification of Key Small Non‐Coding MicroRNAs Controlling Pacemaker Mechanisms in the Human Sinus NodeMaria Petkova0Andrew J. Atkinson1Joseph Yanni2Luke Stuart3Abimbola J. Aminu4Alexandra D. Ivanova5Ksenia B. Pustovit6Connor Geragthy7Amy Feather8Ning Li9Yu Zhang10Delvac Oceandy11Filip Perde12Peter Molenaar13Alicia D’Souza14Vadim V. Fedorov15Halina Dobrzynski16Division of Cardiovascular Sciences University of Manchester United KingdomDivision of Cardiovascular Sciences University of Manchester United KingdomDivision of Cardiovascular Sciences University of Manchester United KingdomDivision of Cardiovascular Sciences University of Manchester United KingdomDivision of Cardiovascular Sciences University of Manchester United KingdomDepartment of Human and Animal Physiology Lomonosov Moscow State University Moscow RussiaDepartment of Human and Animal Physiology Lomonosov Moscow State University Moscow RussiaDivision of Cardiovascular Sciences University of Manchester United KingdomDivision of Cardiovascular Sciences University of Manchester United KingdomPhysiology and Cell Biology Department The Bob and Corrine Frick Center for Heart Failure and Arrhythmia The Ohio State University Wexner Medical Center Columbus OHDivision of Cardiovascular Sciences University of Manchester United KingdomDivision of Cardiovascular Sciences University of Manchester United KingdomNational Institute of Legal Medicine Bucharest RomaniaSchool of Biomedical Sciences Queensland University of Technology Brisbane AustraliaDivision of Cardiovascular Sciences University of Manchester United KingdomPhysiology and Cell Biology Department The Bob and Corrine Frick Center for Heart Failure and Arrhythmia The Ohio State University Wexner Medical Center Columbus OHDivision of Cardiovascular Sciences University of Manchester United KingdomBackground 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 Ca2+‐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 (Cav)1.3, and Cav3.1. 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.https://www.ahajournals.org/doi/10.1161/JAHA.120.016590ion channelsmicroRNAspacemaker of the heartsinus node disease |
| spellingShingle | Maria Petkova Andrew J. Atkinson Joseph Yanni Luke Stuart Abimbola J. Aminu Alexandra D. Ivanova Ksenia B. Pustovit Connor Geragthy Amy Feather Ning Li Yu Zhang Delvac Oceandy Filip Perde Peter Molenaar Alicia D’Souza Vadim V. Fedorov Halina Dobrzynski Identification of Key Small Non‐Coding MicroRNAs Controlling Pacemaker Mechanisms in the Human Sinus Node Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease ion channels microRNAs pacemaker of the heart sinus node disease |
| title | Identification of Key Small Non‐Coding MicroRNAs Controlling Pacemaker Mechanisms in the Human Sinus Node |
| title_full | Identification of Key Small Non‐Coding MicroRNAs Controlling Pacemaker Mechanisms in the Human Sinus Node |
| title_fullStr | Identification of Key Small Non‐Coding MicroRNAs Controlling Pacemaker Mechanisms in the Human Sinus Node |
| title_full_unstemmed | Identification of Key Small Non‐Coding MicroRNAs Controlling Pacemaker Mechanisms in the Human Sinus Node |
| title_short | Identification of Key Small Non‐Coding MicroRNAs Controlling Pacemaker Mechanisms in the Human Sinus Node |
| title_sort | identification of key small non coding micrornas controlling pacemaker mechanisms in the human sinus node |
| topic | ion channels microRNAs pacemaker of the heart sinus node disease |
| url | https://www.ahajournals.org/doi/10.1161/JAHA.120.016590 |
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