title: miR-208b upregulation interferes with calcium handling in HL-1 atrial myocytes: Implications in human chronic atrial fibrillation.
abstract: 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 clearly pointed to CAF-specific upregulated miR-208b as an important mediator in Ca2+handling impairment during atrial remodeling.
authors.affiliation: Cardiovascular Development and Repair Department, Spanish National Cardiovascular Research Center (CNIC), Madrid, Spain; Department of Immunology and Oncology, Centro Nacional de Biotecnología (CNB-CSIC), Madrid, Spain.
authors.forename: Susana
authors.initials: S
authors.lastname: Cañón
authors.affiliation: Department of Pharmacology, School of Medicine, Universidad Complutense, 28040 Madrid, Spain.
authors.forename: Ricardo
authors.initials: R
authors.lastname: Caballero
authors.affiliation: Cardiovascular Research Centre, CSIC-ICCC, Barcelona, Spain; Instituto de Investigación Biomédica Sant Pau, Hospital de la Santa Creu y Sant Pau, Barcelona, Spain.
authors.forename: Adela
authors.initials: A
authors.lastname: Herraiz-Martínez
authors.affiliation: Department of Pharmacology, School of Medicine, Universidad Complutense, 28040 Madrid, Spain.
authors.forename: Marta
authors.initials: M
authors.lastname: Pérez-Hernández
authors.affiliation: Program for Cardiovascular Diseases, Centre for Applied Medical Research, University of Navarra, Pamplona, Spain; Instituto de Investigación Sanitaria de Navarra (IdiSNA), Pamplona, Spain.
authors.forename: Begoña
authors.initials: B
authors.lastname: López
authors.affiliation: Cardiology Department, Hospital General Universitario Gregorio Marañón, Madrid, Spain.
authors.forename: Felipe
authors.initials: F
authors.lastname: Atienza
authors.affiliation: Center for Arrhythmia Research, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA; Area of Myocardial Pathophysiology, Spanish National Cardiovascular Research Center (CNIC), Madrid, Spain.
authors.forename: José
authors.initials: J
authors.lastname: Jalife
authors.affiliation: Cardiovascular Research Centre, CSIC-ICCC, Barcelona, Spain; Instituto de Investigación Biomédica Sant Pau, Hospital de la Santa Creu y Sant Pau, Barcelona, Spain.
authors.forename: Leif
authors.initials: L
authors.lastname: Hove-Madsen
authors.affiliation: Department of Pharmacology, School of Medicine, Universidad Complutense, 28040 Madrid, Spain.
authors.forename: Eva
authors.initials: E
authors.lastname: Delpón
authors.affiliation: Cardiovascular Development and Repair Department, Spanish National Cardiovascular Research Center (CNIC), Madrid, Spain; Department of Immunology and Oncology, Centro Nacional de Biotecnología (CNB-CSIC), Madrid, Spain. Electronic address: abernad@cnb.csic.es.
authors.forename: Antonio
authors.initials: A
authors.lastname: Bernad
mesh_terms: D020413:3' Untranslated Regions; D000818:Animals; D001281:Atrial Fibrillation / Q000235:genetics* / Q000378:metabolism* / Q000503:physiopathology; D064752:Atrial Remodeling; D001483:Base Sequence; D002118:Calcium / Q000378:metabolism*; D020746:Calcium Channels, L-Type / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D002908:Chronic Disease; D018031:Connexin 43 / Q000378:metabolism; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006325:Heart Atria / Q000166:cytology* / Q000378:metabolism* / Q000503:physiopathology; D006801:Humans; D035683:MicroRNAs / Q000235:genetics*; D032383:Myocytes, Cardiac / Q000378:metabolism*; D009218:Myosins / Q000235:genetics; D011485:Protein Binding; D034622:RNA Interference; D012333:RNA, Messenger / Q000235:genetics; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000378:metabolism; D012756:Sheep; D051153:Wnt Proteins / Q000378:metabolism
chemical_list: D020413:3' Untranslated Regions; D020746:Calcium Channels, L-Type; D018031:Connexin 43; C550906:MIRN208 microRNA, human; D035683:MicroRNAs; D012333:RNA, Messenger; D051153:Wnt Proteins; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D009218:Myosins; D002118:Calcium
keywords: Ca(2+) remodeling; Connexin 43; I(Ca,L); MYH7; SERCA2; miR-208a