Transgenic mice overexpressing desmocollin-2 (DSC2) develop cardiomyopathy associated with myocardial inflammation and fibrotic remodeling.
BACKGROUND
Arrhythmogenic cardiomyopathy is an inherited heart muscle disorder leading to ventricular arrhythmias and heart failure, mainly as a result of mutations in cardiac desmosomal genes. Desmosomes are cell-cell junctions mediating adhesion of cardiomyocytes; however, the molecular and cellular mechanisms underlying the disease remain widely unknown. Desmocollin-2 is a desmosomal cadherin serving as an anchor molecule required to reconstitute homeostatic intercellular adhesion with desmoglein-2. Cardiac specific lack of desmoglein-2 leads to severe cardiomyopathy, whereas overexpression does not. In contrast, the corresponding data for desmocollin-2 are incomplete, in particular from the view of protein overexpression. Therefore, we developed a mouse model overexpressing desmocollin-2 to determine its potential contribution to cardiomyopathy and intercellular adhesion pathology.


RESULTS
We generated transgenic mice overexpressing DSC2 in cardiac myocytes. Transgenic mice developed a severe cardiac dysfunction over 5 to 13 weeks as indicated by 2D-echocardiography measurements. Corresponding histology and immunohistochemistry demonstrated fibrosis, necrosis and calcification which were mainly localized in patches near the epi- and endocardium of both ventricles. Expressions of endogenous desmosomal proteins were markedly reduced in fibrotic areas but appear to be unchanged in non-fibrotic areas. Furthermore, gene expression data indicate an early up-regulation of inflammatory and fibrotic remodeling pathways between 2 to 3.5 weeks of age.


CONCLUSIONS
Cardiac specific overexpression of desmocollin-2 induces necrosis, acute inflammation and patchy cardiac fibrotic remodeling leading to fulminant biventricular cardiomyopathy.
Department of Cardiac Sciences and Libin Cardiovascular Institute of Alberta, University of Calgary, Calgary, Alberta, Canada.
Andreas
A
Brodehl
Department of Cardiac Sciences and Libin Cardiovascular Institute of Alberta, University of Calgary, Calgary, Alberta, Canada.
Darrell D
DD
Belke
Department of Cardiac Sciences and Libin Cardiovascular Institute of Alberta, University of Calgary, Calgary, Alberta, Canada.
Lauren
L
Garnett
Department of Cardiac Sciences and Libin Cardiovascular Institute of Alberta, University of Calgary, Calgary, Alberta, Canada.
Kristina
K
Martens
Department of Cardiac Sciences and Libin Cardiovascular Institute of Alberta, University of Calgary, Calgary, Alberta, Canada.
Nelly
N
Abdelfatah
Department of Cardiac Sciences and Libin Cardiovascular Institute of Alberta, University of Calgary, Calgary, Alberta, Canada.|Schulich School of Engineering, University of Calgary, Calgary, Alberta, Canada.
Marcela
M
Rodriguez
Department of Cardiac Sciences and Libin Cardiovascular Institute of Alberta, University of Calgary, Calgary, Alberta, Canada.
Catherine
C
Diao
Department of Cardiac Sciences and Libin Cardiovascular Institute of Alberta, University of Calgary, Calgary, Alberta, Canada.
Yong-Xiang
YX
Chen
Alberta Children's Hospital Research Institute Genomics and Bioinformatics Facility, University of Calgary, Calgary, Alberta, Canada.
Paul M K
PM
Gordon
Department of Cardiac Sciences and Libin Cardiovascular Institute of Alberta, University of Calgary, Calgary, Alberta, Canada.|Schulich School of Engineering, University of Calgary, Calgary, Alberta, Canada.
Anders
A
Nygren
Department of Cardiac Sciences and Libin Cardiovascular Institute of Alberta, University of Calgary, Calgary, Alberta, Canada.|Comprehensive Heart Failure Center and Department of Internal Medicine I, University Hospital Würzburg, Würzburg, Germany.
Brenda
B
Gerull
D000818:Animals; D009202:Cardiomyopathies / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D051187:Desmocollins; D003896:Desmosomes / Q000378:metabolism; D005355:Fibrosis / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008562:Membrane Glycoproteins / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009205:Myocarditis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D009206:Myocardium / Q000378:metabolism / Q000473:pathology*; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000473:pathology*; D015854:Up-Regulation
D051187:Desmocollins; C489912:Dsc2 protein, mouse; D008562:Membrane Glycoproteins