title: High-fat diet increases vulnerability to atrial arrhythmia by conduction disturbance via miR-27b.
abstract: BACKGROUND
  Lifestyle-related diseases, such as obesity and dyslipidemia are important risk factors for atrial fibrillation (AF). However, the underlying mechanism linking these diseases and AF has not been fully investigated.
  
  
  METHODS
  Adult male mice were fed a high-fat diet (HFD) or vehicle (NC) for 2 months. Electrocardiography and in vivo electrophysiological study were performed. Mice were then sacrificed for quantification of mRNA, microRNA, and protein in atria, in addition to histological analysis. Conduction velocity (CV) in right atrium was measured by optical mapping in Langendorff perfused hearts. Cultured atrial cardiomyocytes were treated with palmitate with or without a specific microRNA inhibitor. Twelve hours after stimulation, cells were lysed, and subjected to analysis with qPCR and Western blotting.
  
  
  RESULTS
  HFD mice showed prolonged P wave duration, increased inducibility of sustained atrial tachycardia, and reduced atrial CV than NC mice. HFD mice also showed increased expression in inflammatory cytokines, whereas fibrotic area and signals relating fibrosis were not changed. HFD mice demonstrated reduced expression of Cx40 in mRNA and protein levels, and its lateralized expression in atria. MicroRNA array analysis revealed that miR-27b expression was up-regulated in HFD mice, and luciferase assay confirmed the direct interaction between miR-27b and Cx40 3'UTR. In palmitate-stimulated atrial cardiomyocytes, miR-27b up-regulation and Cx40 down-regulation were observed, while expression of inflammatory cytokines was not altered. Inhibition of miR-27b with antisense oligonucleotides reversed the alteration caused by palmitate stimulation.
  
  
  CONCLUSIONS
  HFD may increase the vulnerability to atrial arrhythmia by down-regulation of Cx40 via miR-27b, rather than fibrosis, which is independent of inflammation.
authors.affiliation: Department of Cardiovascular Medicine, Tokyo Medical and Dental University School of Medicine, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan.
authors.forename: Kentaro
authors.initials: K
authors.lastname: Takahashi
authors.affiliation: Department of Biofunctional Informatics, Tokyo Medical and Dental University School of Health Care Sciences, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8519, Japan. Electronic address: sasano.bi@tmd.ac.jp.
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Sasano
authors.affiliation: Department of Cardiovascular Medicine, Tokyo Medical and Dental University School of Medicine, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan.
authors.forename: Koji
authors.initials: K
authors.lastname: Sugiyama
authors.affiliation: Department of Bio-informational Pharmacology, Medical Research Institute, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan.
authors.forename: Junko
authors.initials: J
authors.lastname: Kurokawa
authors.affiliation: Department of Cardiovascular Medicine, Tokyo Medical and Dental University School of Medicine, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan.
authors.forename: Noriko
authors.initials: N
authors.lastname: Tamura
authors.affiliation: Department of Molecular Pathology, Tokyo Medical and Dental University School of Health Care Sciences, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan.
authors.forename: Yurie
authors.initials: Y
authors.lastname: Soejima
authors.affiliation: Department of Molecular Pathology, Tokyo Medical and Dental University School of Health Care Sciences, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan.
authors.forename: Motoji
authors.initials: M
authors.lastname: Sawabe
authors.affiliation: Department of Cardiovascular Medicine, Tokyo Medical and Dental University School of Medicine, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan.
authors.forename: Mitsuaki
authors.initials: M
authors.lastname: Isobe
authors.affiliation: Department of Bio-informational Pharmacology, Medical Research Institute, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan.
authors.forename: Tetsushi
authors.initials: T
authors.lastname: Furukawa
mesh_terms: D020413:3' Untranslated Regions; D000818:Animals; D001146:Arrhythmia, Sinus / Q000209:etiology / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D053840:Brugada Syndrome / Q000209:etiology / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D000075224:Cardiac Conduction System Disease; D002460:Cell Line; D017630:Connexins / Q000235:genetics* / Q000378:metabolism; D059305:Diet, High-Fat / Q000009:adverse effects*; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D006325:Heart Atria / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D009924:Organ Culture Techniques; D019308:Palmitic Acid / Q000494:pharmacology; D015398:Signal Transduction; D000097003:Gap Junction alpha-5 Protein
chemical_list: D020413:3' Untranslated Regions; D017630:Connexins; D035683:MicroRNAs; D019308:Palmitic Acid; D000097003:Gap Junction alpha-5 Protein; C540674:Mirn27 microRNA, mouse
keywords: Atrial fibrillation; Electrical remodeling; Gap junction; Lipids; MicroRNA