title: Alterations in adhesion junction precede gap junction remodelling during the development of heart failure in cardiomyopathic hamsters.
abstract: OBJECTIVE
  The intercalated disc (ID) contains two complexes, the adhesion junction (AJ) and the gap junction (GJ). We studied ID remodelling and its potential role in arrhythmogenesis and investigated the effects of olmesartan on ID remodelling during development of heart failure (HF) in UM-X7.1 cardiomyopathic hamsters.
  
  
  RESULTS
  The UM-X7.1 hamsters showed left ventricular (LV) hypertrophy by the age of 10-15 weeks and a moderate impairment in LV contractility at 20 weeks. At age 10-15 weeks, 10-20% of the hamsters died suddenly without HF, and ventricular tachycardia (VT)/ventricular fibrillation (VF) was induced in ∼30% of hamsters. Electron microscopy showed that density linking cell-to-cell adhesion was irregular and unclearly defined, and filamentous structures attached to electron-dense components were arranged in disorder. Western blotting showed that the total cellular expression level of β-catenin was decreased, and expression of nuclear β-catenin, which functions as a T-cell factor/lymphocyte enhancer binding factor transcriptional activator, was also remarkably decreased. At age 20 weeks, LV connexin43 expression showed a remarkable decrease, and the VT/VF induction rate was ∼90%. In UM-X7.1 hamsters, olmesartan improved abnormal ID ultrastructural changes, attenuated the decrease of total cellular and nuclear β-catenin expression, decreased VT/VF induction, and improved survival rate.
  
  
  CONCLUSIONS
  These results suggest that changes in AJ protein precede connexin43 GJ alterations, and ID remodelling might contribute to arrhythmogenesis during the development of HF. Angiotensin receptor blockade might be a new therapy for lethal ventricular arrhythmia by modulating both AJ and GJ remodelling.
authors.affiliation: Division of Cardiology, Department of Medicine and Clinical Science, Yamaguchi University Graduate School of Medicine, 1-1-1, Minami-kogushi, Ube, Yamaguchi 755-8505, Japan.
authors.forename: Masaaki
authors.initials: M
authors.lastname: Yoshida
authors.forename: Tomoko
authors.initials: T
authors.lastname: Ohkusa
authors.forename: Tadamitsu
authors.initials: T
authors.lastname: Nakashima
authors.forename: Hiroki
authors.initials: H
authors.lastname: Takanari
authors.forename: Masafumi
authors.initials: M
authors.lastname: Yano
authors.forename: Genzou
authors.initials: G
authors.lastname: Takemura
authors.forename: Haruo
authors.initials: H
authors.lastname: Honjo
authors.forename: Itsuo
authors.initials: I
authors.lastname: Kodama
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Mizukami
authors.forename: Masunori
authors.initials: M
authors.lastname: Matsuzaki
mesh_terms: D022005:Adherens Junctions / Q000502:physiology*; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000209:etiology; D015820:Cadherins / Q000032:analysis; D009202:Cardiomyopathies / Q000503:physiopathology*; D018031:Connexin 43 / Q000032:analysis; D006224:Cricetinae; D004452:Echocardiography; D024202:Electrophoretic Mobility Shift Assay; D017629:Gap Junctions / Q000502:physiology*; D038362:Glycogen Synthase Kinase 3 / Q000502:physiology; D000071679:Glycogen Synthase Kinase 3 beta; D006333:Heart Failure / Q000503:physiopathology*; D008647:Mesocricetus; D009206:Myocardium / Q000473:pathology / Q000648:ultrastructure; D051176:beta Catenin / Q000032:analysis
chemical_list: D015820:Cadherins; D018031:Connexin 43; D051176:beta Catenin; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3