title: Remodeling of gap junctions and slow conduction in a mouse model of desmin-related cardiomyopathy.
abstract: OBJECTIVE
  We studied a transgenic mouse model of human desmin-related cardiomyopathy with cardiac-specific expression of a 7-amino acid deletion mutation in desmin (D7-des) to test the hypothesis that impaired linkage between desmin and desmosomes alters expression and function of the electrical coupling protein, connexin43 (Cx43).
  
  
  METHODS
  Expression of Cx43 and selected mechanical junctions proteins was characterized in left ventrices of D7-des and control mice by quantitative confocal microscopy and immunoblotting. Remodeling of gap junctions was also analyzed by electron microscopic morphometry. The electrophysiological phentoype of D7-des mice was characterized by electrocardiography and optical mapping of transmembrane voltage.
  
  
  RESULTS
  Cx43 signal at intercalated disks was decreased by approximately 3-fold in D7-des ventricular tissue due to reductions in both gap junction number and size. Immunoreactive signal at cell-cell junctions was also reduced significantly for adhesion molecules and linker proteins of desmosomes and fascia adherens junctions. Electron microscopy showed decreased gap junction remodeling. However, immunoblotting showed that the total tissue content of Cx43 and mechanical junction proteins was not reduced, suggesting that diminished signal at cell-cell junctions was not due to insufficient protein expression, but to failure of these proteins to assemble properly within electrical and mechanical junctions. Remodeling of gap junctions in D7-des mice led to slowing of ventricular conduction as demonstrated by optical electrophysiological mapping.
  
  
  CONCLUSIONS
  These results illustrate how a defect in a protein conventionally thought to fulfill a mechanical function in the heart can also lead to electrophysiological alterations that may contribute to arrhythmogenesis.
authors.affiliation: Department of Pathology, Box 8118, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, MO 63110, USA.
authors.forename: Joseph J
authors.initials: JJ
authors.lastname: Gard
authors.forename: Kiyomi
authors.initials: K
authors.lastname: Yamada
authors.forename: Karen G
authors.initials: KG
authors.lastname: Green
authors.forename: Benjamin C
authors.initials: BC
authors.lastname: Eloff
authors.forename: David S
authors.initials: DS
authors.lastname: Rosenbaum
authors.forename: Xuejun
authors.initials: X
authors.lastname: Wang
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Robbins
authors.forename: Richard B
authors.initials: RB
authors.lastname: Schuessler
authors.forename: Kathryn A
authors.initials: KA
authors.lastname: Yamada
authors.forename: Jeffrey E
authors.initials: JE
authors.lastname: Saffitz
mesh_terms: D000818:Animals; D009202:Cardiomyopathies / Q000378:metabolism* / Q000503:physiopathology; D003893:Desmin / Q000032:analysis / Q000235:genetics* / Q000378:metabolism; D004594:Electrophysiology; D017629:Gap Junctions / Q000737:chemistry* / Q000378:metabolism; D007150:Immunohistochemistry / Q000379:methods; D051379:Mice; D008822:Mice, Transgenic; D018613:Microscopy, Confocal; D008856:Microscopy, Fluorescence; D023421:Models, Animal; D009154:Mutation; D009200:Myocardial Contraction; D032383:Myocytes, Cardiac / Q000737:chemistry* / Q000378:metabolism
chemical_list: D003893:Desmin