title: A MicroRNA-Transcription Factor Blueprint for Early Atrial Arrhythmogenic Remodeling.
abstract: Spontaneous self-terminating atrial fibrillation (AF) is one of the most common heart rhythm disorders, yet the regulatory molecular mechanisms underlying this syndrome are rather unclear. MicroRNA (miRNA) transcriptome and expression of candidate transcription factors (TFs) with potential roles in arrhythmogenesis, such as Pitx2, Tbx5, and myocardin (Myocd), were analyzed by microarray, qRT-PCR, and Western blotting in left atrial (LA) samples from pigs with transitory AF established by right atrial tachypacing. Induced ectopic tachyarrhythmia caused rapid and substantial miRNA remodeling associated with a marked downregulation of Pitx2, Tbx5, and Myocd expression in atrial myocardium. The downregulation of Pitx2, Tbx5, and Myocd was inversely correlated with upregulation of the corresponding targeting miRNAs (miR-21, miR-10a/10b, and miR-1, resp.) in the LA of paced animals. Through in vitro transient transfections of HL-1 atrial myocytes, we further showed that upregulation of miR-21 did result in downregulation of Pitx2 in cardiomyocyte background. The results suggest that immediate-early miRNA remodeling coupled with deregulation of TF expression underlies the onset of AF.
authors.affiliation: Institute of Health Sciences, University of La Coruña, 15006 La Coruña, Spain.
authors.forename: Mario
authors.initials: M
authors.lastname: Torrado
authors.affiliation: Department of Experimental Biology, University of Jaén, Jaén, Spain.
authors.forename: Diego
authors.initials: D
authors.lastname: Franco
authors.affiliation: Department of Experimental Biology, University of Jaén, Jaén, Spain.
authors.forename: Estefanía
authors.initials: E
authors.lastname: Lozano-Velasco
authors.affiliation: Department of Experimental Biology, University of Jaén, Jaén, Spain.
authors.forename: Francisco
authors.initials: F
authors.lastname: Hernández-Torres
authors.affiliation: University Hospital Center of La Coruña, La Coruña, Spain.
authors.forename: Ramón
authors.initials: R
authors.lastname: Calviño
authors.affiliation: University Hospital Center of La Coruña, La Coruña, Spain.
authors.forename: Guillermo
authors.initials: G
authors.lastname: Aldama
authors.affiliation: University Hospital Center of La Coruña, La Coruña, Spain.
authors.forename: Alberto
authors.initials: A
authors.lastname: Centeno
authors.affiliation: Institute of Health Sciences, University of La Coruña, 15006 La Coruña, Spain.
authors.forename: Alfonso
authors.initials: A
authors.lastname: Castro-Beiras
authors.affiliation: Institute of Health Sciences, University of La Coruña, 15006 La Coruña, Spain.
authors.forename: Alexander
authors.initials: A
authors.lastname: Mikhailov
mesh_terms: D000818:Animals; D001145:Arrhythmias, Cardiac / Q000235:genetics* / Q000503:physiopathology; D001281:Atrial Fibrillation / Q000235:genetics / Q000473:pathology; D064752:Atrial Remodeling / Q000235:genetics*; D015870:Gene Expression; D006325:Heart Atria / Q000473:pathology; D018398:Homeodomain Proteins / Q000235:genetics; D006801:Humans; D035683:MicroRNAs / Q000096:biosynthesis* / Q000235:genetics; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000473:pathology; D013552:Swine; D014157:Transcription Factors / Q000096:biosynthesis* / Q000235:genetics; D059467:Transcriptome / Q000235:genetics*; D000097577:Homeobox Protein PITX2
chemical_list: D018398:Homeodomain Proteins; D035683:MicroRNAs; D014157:Transcription Factors; D000097577:Homeobox Protein PITX2