Regulation of SCN5A by microRNAs: miR-219 modulates SCN5A transcript expression and the effects of flecainide intoxication in mice.
Background: The human cardiac action potential in atrial and ventricular cells is initiated by a fast-activating, fast-inactivating sodium current generated by the SCN5A/Nav1.5 channel in association with its β1/SCN1B subunit. The role of Nav1.5 in the etiology of many cardiac diseases strongly sugg...
| Publicado en: | Heart Rhythm Vol. 12; no. 6; pp. 1333 - 1343 |
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| Autores principales: | , , , , , , , , , |
| Formato: | research Journal Article |
| Publicado: |
Elsevier B.V.
Jun2015
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| Acceso en línea: | Ver este registro en EBSCOhost |
| fields | @attributes: recordID: 1 pdfLink: plink: https://search.ebscohost.com/login.aspx?direct=true&db=ccm&AN=109738382&site=ehost-live header: @attributes: shortDbName: ccm uiTerm: 109738382 longDbName: CINAHL Complete uiTag: AN controlInfo: bkinfo: dissinfo: jinfo: jid: 15475271 EHI jtl: Heart Rhythm issn: 15475271 maglogo: N pubinfo: dt: Jun2015 vid: 12 iid: 6 pid: 467 pub: Elsevier B.V. place: New York, New York artinfo: ui: 109738382 NLM25701775 2013020493 10.1016/j.hrthm.2015.02.018 NLM25701775 109738382 ppf: 1333 ppct: 10 formats: tig: atl: Regulation of SCN5A by microRNAs: miR-219 modulates SCN5A transcript expression and the effects of flecainide intoxication in mice. aug: au: Daimi, Houria Lozano-Velasco, Estefania Haj Khelil, Amel Chibani, Jemni B E Barana, Adriana Amorós, Irene González de la Fuente, Marta Caballero, Ricardo Aranega, Amelia Franco, Diego sug: ab: Background: The human cardiac action potential in atrial and ventricular cells is initiated by a fast-activating, fast-inactivating sodium current generated by the SCN5A/Nav1.5 channel in association with its β1/SCN1B subunit. The role of Nav1.5 in the etiology of many cardiac diseases strongly suggests that proper regulation of cell biology and function of the channel is critical for normal cardiac function. Hence, numerous recent studies have focused on the regulatory mechanisms of Nav1.5 biosynthetic and degradation processes as well as its subcellular localization.Objective: The purpose of this study was to investigate the role of microRNAs in the Scn5a/Nav1.5 posttranscriptional regulation.Methods: Quantitative polymerase chain reaction, immunohistochemical and electrophysiological measurements of distinct microRNA gain-of-function experiments in cardiomyocytes for the assessment of Scn5a expression.Results: Functional studies of HL-1 cardiomyocytes and luciferase assays in fibroblasts demonstrate that Scn5a is directly (miR-98, miR-106, miR-200, and miR-219) and indirectly (miR-125 and miR-153) regulated by multiple microRNAs displaying distinct time-dependent profiles. Cotransfection experiments demonstrated that miR-219 and miR-200 have independent opposite effects on Scn5a expression modulation. Of all the microRNAs studied, only miR-219 increases Scn5a expression levels, leading to altered contraction rhythm of HL-1 cardiomyocytes. Electrophysiological analyses in HL-1 cells revealed that miR-219 increases the sodium current. In vivo administration of miR-219 does not alter normal cardiac rhythm, but abolishes some of the effects of flecainide intoxication in mice, particularly QRS prolongation.Conclusion: This study demonstrates the involvement of multiple microRNAs in the regulation of Scn5a. Particularly, miR-219 increases Scn5a/Nav1.5 transcript and protein expression. Our data suggest that microRNAs, such as miR-219, constitute a promising therapeutical tool to treat sodium cardiac arrhythmias. pubtype: Academic Journal doctype: research Journal Article ougenre: Article language: English refInfo: holdings: @attributes: islocal: N |
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