Journal
JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY
Volume 99, Issue -, Pages 162-173Publisher
ELSEVIER SCI LTD
DOI: 10.1016/j.yjmcc.2016.08.012
Keywords
miR-208a; MYH7; Connexin 43; Ca2+ remodeling; I-Ca,I-L; SERCA2
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Funding
- Spanish Ministry of Science and Innovation [SAF2012-34327, PLE2009-0147]
- Ministry of Economy and Competitiveness [SAF2014-58769-P, SAF2014-58286-C2-1-R]
- Institute de Salud Carlos III [RETICS-RD12/0019/0018, RD12/0042/0011]
- research program of the Comunidad Autonoma de Madrid [S2010/BMD-2420, S2010/BMD-2374]
- European Commission [242038]
- National Heart, Lung and Blood Institute R01 [HL122352]
- Fondation Leducq
- University of Michigan Health System-Peking University Health Science Center Joint Institute for Translational and Clinical Research
- Pro-CNIC Foundation intramural program grant [CNIC08-2009]
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MicroRNAs (miR) have considerable potential as therapeutic tools in cardiac diseases. Alterations in atrial miR are involved in the development of atrial fibrillation (AF), but the molecular mechanism underlying their contribution to atrial remodeling in chronic atrial fibrillation (CAF) is only partially understood. Here we used miR array to analyze the miR profile of atrial biopsies from sinus rhythm (SR) and CAF patients. qRT-PCR identified a distinctive CAF-miR signature and described conserved miR-208b upregulation in human and ovine AF atrial tissue. We used bioinformatics analysis to predict genes and signaling pathways as putative miR-208b targets, which highlighted genes from the cardiac muscle gene program and from canonical WNT, gap junction and Ca2+ signaling networks. Results from analysis of miR-208b-overexpressing HL-1 atrial myocytes and from myocytes isolated from CAF patients showed that aberrant miR-208b levels reduced the expression and function of L-type Ca2+ channel subunits (CACNA1C and CACNB2) as well as the sarcoplasmic reticulum-Ca2+ pump SERCA2. These findings dearly pointed to CAF-specific upregulated miR-208b as an important mediator in Ca2+ handling impairment during atrial remodeling. (C) 2016 Elsevier Ltd. All rights reserved.
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