title: Identification of microRNA-mRNA dysregulations in paroxysmal atrial fibrillation.
abstract: BACKGROUND
  The molecular mechanisms underlying the early development of atrial fibrillation (AF) remain poorly understood. Emerging evidence suggests that abnormal epigenetic modulation via microRNAs (miRNAs) might be involved in the pathogenesis of paroxysmal AF (pAF).
  
  
  OBJECTIVE
  To identify key molecular changes associated with pAF, we conducted state-of-the-art transcriptomic studies to identify the abnormal miRNA-mRNA interactions potentially driving AF development.
  
  
  METHODS
  High-quality total RNA including miRNA was isolated from atrial biopsies of age-matched and sex-matched pAF patients and control patients in sinus rhythm (SR; n=4 per group) and used for RNA-sequencing and miRNA microarray. Results were analyzed bioinformatically and validated using quantitative real-time (qRT)-PCR and 3'UTR luciferase reporter assays.
  
  
  RESULTS
  113 genes and 49 miRNAs were differentially expressed (DE) in pAF versus SR patients. Gene ontology analysis revealed that most of the DE genes were involved in the "gonadotropin releasing hormone receptor pathway" and "p53 pathway". Of these DE genes, bioinformatic analyses identified 23 pairs of putative miRNA-mRNA interactions that were altered in pAF (involving 15 miRNAs and 17 mRNAs). Using qRT-PCR and 3'UTR luciferase reporter assays, the interaction between upregulation of miR-199a-5p and downregulation of FKBP5 was confirmed in samples from pAF patients.
  
  
  CONCLUSIONS
  Our combined transcriptomic analysis and miRNA microarray study of atrial samples from pAF patients revealed novel pathways and miRNA-mRNA regulations that may be relevant in the development of pAF. Future studies are required to investigate the potential involvement of the gonadotropin releasing hormone receptor and p53 pathways in AF pathogenesis.
authors.affiliation: Cardiovascular Research Institute, Baylor College of Medicine, Houston, TX, USA; Department of Molecular Physiology & Biophysics, Baylor College of Medicine, Houston, TX, USA.
authors.forename: David Y
authors.initials: DY
authors.lastname: Chiang
authors.affiliation: Department of Molecular Physiology & Biophysics, Baylor College of Medicine, Houston, TX, USA.
authors.forename: Min
authors.initials: M
authors.lastname: Zhang
authors.affiliation: Institute of Pharmacology, Faculty of Medicine, University Duisburg-Essen, Essen, Germany.
authors.forename: Niels
authors.initials: N
authors.lastname: Voigt
authors.affiliation: Integrative Molecular and Biomedical Sciences Program, Baylor College of Medicine, Houston, TX, USA.
authors.forename: Katherina M
authors.initials: KM
authors.lastname: Alsina
authors.affiliation: Department of Thoracic and Cardiovascular Surgery, University Hospital, Essen, Germany.
authors.forename: Heinz
authors.initials: H
authors.lastname: Jakob
authors.affiliation: Department of Molecular Physiology & Biophysics, Baylor College of Medicine, Houston, TX, USA; Texas Heart Institute Houston, TX, USA.
authors.forename: James F
authors.initials: JF
authors.lastname: Martin
authors.affiliation: Institute of Pharmacology, Faculty of Medicine, University Duisburg-Essen, Essen, Germany.
authors.forename: Dobromir
authors.initials: D
authors.lastname: Dobrev
authors.affiliation: Cardiovascular Research Institute, Baylor College of Medicine, Houston, TX, USA; Department of Molecular Physiology & Biophysics, Baylor College of Medicine, Houston, TX, USA; Department of Medicine (Cardiology), Baylor College of Medicine, Houston, TX, USA.
authors.forename: Xander H T
authors.initials: XHT
authors.lastname: Wehrens
authors.affiliation: Cardiovascular Research Institute, Baylor College of Medicine, Houston, TX, USA; Department of Molecular Physiology & Biophysics, Baylor College of Medicine, Houston, TX, USA. Electronic address: nal@bcm.edu.
authors.forename: Na
authors.initials: N
authors.lastname: Li
mesh_terms: D000368:Aged; D001281:Atrial Fibrillation / Q000175:diagnosis* / Q000235:genetics* / Q000503:physiopathology; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods; D006801:Humans; D008297:Male; D035683:MicroRNAs / Q000235:genetics*; D046228:Microarray Analysis / Q000379:methods; D008875:Middle Aged; D012333:RNA, Messenger / Q000235:genetics*
chemical_list: D035683:MicroRNAs; D012333:RNA, Messenger
keywords: Paroxysmal atrial fibrillation; RNA sequencing; Transcriptomic study; microRNA