Copyright © 2005, European Society of Cardiology
Remodeling of gap junctions and slow conduction in a mouse model of desmin-related cardiomyopathy
aDepartment of Pathology, Box 8118, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, MO 63110, USA
bDepartment of Medicine, Washington University School of Medicine, St. Louis, MO, USA
cDepartment of Surgery, Washington University School of Medicine, St. Louis, MO, USA
dHeart and Vascular Research Center, MetroHealth Campus, Case Western Reserve University, Cleveland, OH, USA
eCardiovascular Research Institute, University of South Dakota, School of Medicine, Sioux Falls, SD, USA
fCincinnati Children's Hospital Medical Center, Cincinnati, OH, USA
* Corresponding author. Tel.: +1 314 362 7728; fax: +1 314 362 4096. Email address: saffitz{at}pathology.wustl.edu
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 
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.
KEYWORDS Cardiomyopathy; Cell communication; Cytoskeleton; Gap junctions
1 Current address: University of Nebraska School of Medicine, Omaha, Nebraska, USA.
Time for primary review 15 days
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