Desmoglein 2-Dependent Arrhythmogenic Cardiomyopathy Is Caused by a Loss of Adhesive Function
Sebastian Kant1, Bastian Holthöfer1, Thomas M Magin1
1From the Institute of Molecular and Cellular Anatomy, RWTH Aachen University, Aachen, Germany (S.K., B.H., C.A.K., R.E.L.); and Institute of Biology and Translational Center for Regenerative Medicine, University of Leipzig, Leipzig, Germany (T.M.M.).
Insights
Loss of desmoglein 2 (Dsg2) in cardiomyocytes causes arrhythmogenic cardiomyopathy (AC) in mice, leading to heart failure. This highlights Dsg2's crucial role in maintaining cardiac adhesion and function under mechanical stress.
Area of Science:
- Cardiovascular Biology
- Molecular Cardiology
- Genetic Heart Diseases
Background:
- Desmoglein 2 (Dsg2) is a desmosomal cadherin essential for cardiomyocyte adhesion at intercalated discs.
- Mutations in the DSG2 gene are linked to arrhythmogenic cardiomyopathy (AC) in humans, suggesting a role in cardiac integrity.
- AC is characterized by arrhythmias, heart dilation, and cardiomyocyte death, often associated with intercalated disc abnormalities.
Purpose of the Study:
- To investigate the role of cardiomyocyte-specific desmoglein 2 (Dsg2) in the development of cardiomyopathy.
- To determine if Dsg2 depletion in the heart triggers pathological changes consistent with arrhythmogenic cardiomyopathy.
- To elucidate the pathomechanisms underlying Dsg2-related arrhythmogenic cardiomyopathy.
Main Methods:
- Generation of transgenic mice with cardiomyocyte-specific Dsg2 ablation.
- Assessment of cardiac morphology, function, and protein expression in Dsg2-deficient mice.
- Analysis of intercalated disc structure and desmosome integrity using electron microscopy.
- Evaluation of mice with mutant DSG2 alleles lacking key adhesive domains.
Main Results:
- Cardiomyocyte-specific Dsg2 ablation resulted in mice developing arrhythmogenic cardiomyopathy postnatally.
- Dsg2-deficient hearts showed chamber dilation, cardiomyocyte necrosis, inflammation, and fibrosis.
- Electron microscopy confirmed the absence of desmosome-like structures and loss of intercalated disc adhesion.
- Mice with mutant Dsg2 alleles exhibited a similar phenotype to human AC patients.
Conclusions:
- Desmoglein 2 is not essential for early heart development or basic cardiac function but is critical for maintaining heart integrity under mechanical stress.
- Loss of Dsg2 compromises cardiomyocyte adhesion, representing a key pathogenic mechanism in DSG2-related AC.
- These findings suggest that desmosomal adhesion defects are central to the pathogenesis of various desmosome-related cardiomyopathies.
Background:
The desmosomal cadherin desmoglein 2 (Dsg2) localizes to the intercalated disc coupling adjacent cardiomyocytes. Desmoglein 2 gene (DSG2) mutations cause arrhythmogenic cardiomyopathy (AC) in human and transgenic mice. AC is characterized by arrhythmia, cardiodilation, cardiomyocyte necrosis with replacement fibrosis, interstitial fibrosis, and intercalated disc dissociation. The genetic DSG2 constellations encountered are compatible with loss of adhesion and altered signaling. To further elucidate pathomechanisms, we examined whether heart-specific Dsg2 depletion triggers cardiomyopathy.
Methods And Results:
Because DSG2 knockouts die during early embryogenesis, mice were prepared with cardiomyocyte-specific DSG2 ablation. Healthy transgenic animals were born with a functional heart presenting intercalated discs with incorporated desmosomal proteins. Dsg2 protein expression was reduced below 3% in the heart. All animals developed AC during postnatal growth with pronounced chamber dilation, calcifying cardiomyocyte necrosis, aseptic inflammation, interstitial and focal replacement fibrosis, and conduction defects with altered connexin 43 distribution. Electron microscopy revealed absence of desmosome-like structures and regional loss of intercalated disc adhesion. Mice carrying 2 mutant DSG2 alleles coding for Dsg2 lacking part of the adhesive EC1-EC2 domains present an indistinguishable phenotype, which is similar to that observed in human AC patients.
Conclusions:
The observations show that the presence of Dsg2 is not essential for late heart morphogenesis and for cardiac contractility to support postnatal life. On increasing mechanical demands, heart function is severely compromised as evidenced by the onset of cardiomyopathy with pronounced morphological alterations. We propose that loss of Dsg2 compromises adhesion, and that this is a major pathogenic mechanism in DSG2-related and probably other desmosome-related ACs.
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