title: Chronic atrial fibrillation increases microRNA-21 in human atrial myocytes decreasing L-type calcium current.
abstract: BACKGROUND
  Atrial fibrillation is characterized by progressive atrial structural and electrical changes (atrial remodeling) that favor arrhythmia recurrence and maintenance. Reduction of L-type Ca(2+) current (I(Ca,L)) density is a hallmark of the electrical remodeling. Alterations in atrial microRNAs could contribute to the protein changes underlying atrial fibrillation-induced atrial electrical remodeling. This study was undertaken to compare miR-21 levels in isolated myocytes from atrial appendages obtained from patients in sinus rhythm and with chronic atrial fibrillation (CAF) and to determine whether L-type Ca(2+) channel subunits are targets for miR-21.
  
  
  RESULTS
  Quantitative polymerase chain reaction analysis showed that miR-21 was expressed in human atrial myocytes from patients in sinus rhythm and that its expression was significantly greater in CAF myocytes. There was an inverse correlation between miR-21 and the mRNA of the α1c subunit of the calcium channel (CACNA1C) expression and I(Ca,L) density. Computational analyses predicted that CACNA1C and the mRNA of the β2 subunit of the calcium channel (CACNB2) could be potential targets for miR-21. Luciferase reporter assays demonstrated that miR-21 produced a concentration-dependent decrease in the luciferase activity in Chinese Hamster Ovary cells transfected with CACNA1C and CACNB2 3' untranslated region regions. miR-21 transfection in HL-1 cells produced changes in I(Ca,L) properties qualitatively similar to those produced by CAF (ie, a marked reduction of I(Ca,L) density and shift of the inactivation curves to more depolarized potentials).
  
  
  CONCLUSIONS
  Our results demonstrated that CAF increases miR-21 expression in enzymatically isolated human atrial myocytes. Moreover, it decreases I(Ca,L) density by downregulating Ca(2+) channel subunits expression. These results suggested that this microRNA could participate in the CAF-induced I(Ca,L) downregulation and in the action potential duration shortening that maintains the arrhythmia.
authors.affiliation: From the Department of Pharmacology (A.B., M.M., P.D.-G., M.P.-H., I.A., M.N., S.S., J.T., E.D., R.C.), and Instituto de Investigación Sanitaria Gregorio Marañón (A.B., M.M., P.D.-G., M.P.-H., I.A., M.N., S.S., J.T., E.D., R.C.), School of Medicine, Universidad Complutense de Madrid, Madrid, Spain; and Cardiology and Cardiovascular Surgery Services, Hospital General Universitario Gregorio Marañón, Madrid, Spain (Á.P., Á.P., F.F.-A.).
authors.forename: Adriana
authors.initials: A
authors.lastname: Barana
authors.affiliation: From the Department of Pharmacology (A.B., M.M., P.D.-G., M.P.-H., I.A., M.N., S.S., J.T., E.D., R.C.), and Instituto de Investigación Sanitaria Gregorio Marañón (A.B., M.M., P.D.-G., M.P.-H., I.A., M.N., S.S., J.T., E.D., R.C.), School of Medicine, Universidad Complutense de Madrid, Madrid, Spain; and Cardiology and Cardiovascular Surgery Services, Hospital General Universitario Gregorio Marañón, Madrid, Spain (Á.P., Á.P., F.F.-A.).
authors.forename: Marcos
authors.initials: M
authors.lastname: Matamoros
authors.affiliation: From the Department of Pharmacology (A.B., M.M., P.D.-G., M.P.-H., I.A., M.N., S.S., J.T., E.D., R.C.), and Instituto de Investigación Sanitaria Gregorio Marañón (A.B., M.M., P.D.-G., M.P.-H., I.A., M.N., S.S., J.T., E.D., R.C.), School of Medicine, Universidad Complutense de Madrid, Madrid, Spain; and Cardiology and Cardiovascular Surgery Services, Hospital General Universitario Gregorio Marañón, Madrid, Spain (Á.P., Á.P., F.F.-A.).
authors.forename: Pablo
authors.initials: P
authors.lastname: Dolz-Gaitón
authors.affiliation: From the Department of Pharmacology (A.B., M.M., P.D.-G., M.P.-H., I.A., M.N., S.S., J.T., E.D., R.C.), and Instituto de Investigación Sanitaria Gregorio Marañón (A.B., M.M., P.D.-G., M.P.-H., I.A., M.N., S.S., J.T., E.D., R.C.), School of Medicine, Universidad Complutense de Madrid, Madrid, Spain; and Cardiology and Cardiovascular Surgery Services, Hospital General Universitario Gregorio Marañón, Madrid, Spain (Á.P., Á.P., F.F.-A.).
authors.forename: Marta
authors.initials: M
authors.lastname: Pérez-Hernández
authors.affiliation: From the Department of Pharmacology (A.B., M.M., P.D.-G., M.P.-H., I.A., M.N., S.S., J.T., E.D., R.C.), and Instituto de Investigación Sanitaria Gregorio Marañón (A.B., M.M., P.D.-G., M.P.-H., I.A., M.N., S.S., J.T., E.D., R.C.), School of Medicine, Universidad Complutense de Madrid, Madrid, Spain; and Cardiology and Cardiovascular Surgery Services, Hospital General Universitario Gregorio Marañón, Madrid, Spain (Á.P., Á.P., F.F.-A.).
authors.forename: Irene
authors.initials: I
authors.lastname: Amorós
authors.affiliation: From the Department of Pharmacology (A.B., M.M., P.D.-G., M.P.-H., I.A., M.N., S.S., J.T., E.D., R.C.), and Instituto de Investigación Sanitaria Gregorio Marañón (A.B., M.M., P.D.-G., M.P.-H., I.A., M.N., S.S., J.T., E.D., R.C.), School of Medicine, Universidad Complutense de Madrid, Madrid, Spain; and Cardiology and Cardiovascular Surgery Services, Hospital General Universitario Gregorio Marañón, Madrid, Spain (Á.P., Á.P., F.F.-A.).
authors.forename: Mercedes
authors.initials: M
authors.lastname: Núñez
authors.affiliation: From the Department of Pharmacology (A.B., M.M., P.D.-G., M.P.-H., I.A., M.N., S.S., J.T., E.D., R.C.), and Instituto de Investigación Sanitaria Gregorio Marañón (A.B., M.M., P.D.-G., M.P.-H., I.A., M.N., S.S., J.T., E.D., R.C.), School of Medicine, Universidad Complutense de Madrid, Madrid, Spain; and Cardiology and Cardiovascular Surgery Services, Hospital General Universitario Gregorio Marañón, Madrid, Spain (Á.P., Á.P., F.F.-A.).
authors.forename: Sandra
authors.initials: S
authors.lastname: Sacristán
authors.affiliation: From the Department of Pharmacology (A.B., M.M., P.D.-G., M.P.-H., I.A., M.N., S.S., J.T., E.D., R.C.), and Instituto de Investigación Sanitaria Gregorio Marañón (A.B., M.M., P.D.-G., M.P.-H., I.A., M.N., S.S., J.T., E.D., R.C.), School of Medicine, Universidad Complutense de Madrid, Madrid, Spain; and Cardiology and Cardiovascular Surgery Services, Hospital General Universitario Gregorio Marañón, Madrid, Spain (Á.P., Á.P., F.F.-A.).
authors.forename: Álvaro
authors.initials: Á
authors.lastname: Pedraz
authors.affiliation: From the Department of Pharmacology (A.B., M.M., P.D.-G., M.P.-H., I.A., M.N., S.S., J.T., E.D., R.C.), and Instituto de Investigación Sanitaria Gregorio Marañón (A.B., M.M., P.D.-G., M.P.-H., I.A., M.N., S.S., J.T., E.D., R.C.), School of Medicine, Universidad Complutense de Madrid, Madrid, Spain; and Cardiology and Cardiovascular Surgery Services, Hospital General Universitario Gregorio Marañón, Madrid, Spain (Á.P., Á.P., F.F.-A.).
authors.forename: Ángel
authors.initials: Á
authors.lastname: Pinto
authors.affiliation: From the Department of Pharmacology (A.B., M.M., P.D.-G., M.P.-H., I.A., M.N., S.S., J.T., E.D., R.C.), and Instituto de Investigación Sanitaria Gregorio Marañón (A.B., M.M., P.D.-G., M.P.-H., I.A., M.N., S.S., J.T., E.D., R.C.), School of Medicine, Universidad Complutense de Madrid, Madrid, Spain; and Cardiology and Cardiovascular Surgery Services, Hospital General Universitario Gregorio Marañón, Madrid, Spain (Á.P., Á.P., F.F.-A.).
authors.forename: Francisco
authors.initials: F
authors.lastname: Fernández-Avilés
authors.affiliation: From the Department of Pharmacology (A.B., M.M., P.D.-G., M.P.-H., I.A., M.N., S.S., J.T., E.D., R.C.), and Instituto de Investigación Sanitaria Gregorio Marañón (A.B., M.M., P.D.-G., M.P.-H., I.A., M.N., S.S., J.T., E.D., R.C.), School of Medicine, Universidad Complutense de Madrid, Madrid, Spain; and Cardiology and Cardiovascular Surgery Services, Hospital General Universitario Gregorio Marañón, Madrid, Spain (Á.P., Á.P., F.F.-A.).
authors.forename: Juan
authors.initials: J
authors.lastname: Tamargo
authors.affiliation: From the Department of Pharmacology (A.B., M.M., P.D.-G., M.P.-H., I.A., M.N., S.S., J.T., E.D., R.C.), and Instituto de Investigación Sanitaria Gregorio Marañón (A.B., M.M., P.D.-G., M.P.-H., I.A., M.N., S.S., J.T., E.D., R.C.), School of Medicine, Universidad Complutense de Madrid, Madrid, Spain; and Cardiology and Cardiovascular Surgery Services, Hospital General Universitario Gregorio Marañón, Madrid, Spain (Á.P., Á.P., F.F.-A.) edelpon@med.ucm.es.
authors.forename: Eva
authors.initials: E
authors.lastname: Delpón
authors.affiliation: From the Department of Pharmacology (A.B., M.M., P.D.-G., M.P.-H., I.A., M.N., S.S., J.T., E.D., R.C.), and Instituto de Investigación Sanitaria Gregorio Marañón (A.B., M.M., P.D.-G., M.P.-H., I.A., M.N., S.S., J.T., E.D., R.C.), School of Medicine, Universidad Complutense de Madrid, Madrid, Spain; and Cardiology and Cardiovascular Surgery Services, Hospital General Universitario Gregorio Marañón, Madrid, Spain (Á.P., Á.P., F.F.-A.).
authors.forename: Ricardo
authors.initials: R
authors.lastname: Caballero
mesh_terms: D020413:3' Untranslated Regions; D000200:Action Potentials; D000368:Aged; D020517:Atrial Appendage / Q000378:metabolism* / Q000503:physiopathology; D001281:Atrial Fibrillation / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D001665:Binding Sites; D002118:Calcium / Q000378:metabolism*; D020746:Calcium Channels, L-Type / Q000235:genetics / Q000378:metabolism*; D002908:Chronic Disease; D015536:Down-Regulation; D005260:Female; D017930:Genes, Reporter; D006801:Humans; D008297:Male; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D008875:Middle Aged; D032383:Myocytes, Cardiac / Q000378:metabolism*; D013997:Time Factors; D014162:Transfection; D015854:Up-Regulation
chemical_list: D020413:3' Untranslated Regions; C079146:CACNA1C protein, human; C107597:CACNB2 protein, human; D020746:Calcium Channels, L-Type; C524940:MIRN21 microRNA, human; D035683:MicroRNAs; D002118:Calcium
keywords: atrial fibrillation; calcium channel; human atrial myocytes; miR-21; microRNA