Myocyte necrosis underlies progressive myocardial dystrophy in mouse dsg2-related arrhythmogenic right ventricular cardiomyopathy

Abstract

Mutations in the cardiac desmosomal protein desmoglein-2 (DSG2) are associated with arrhythmogenic right ventricular cardiomyopathy (ARVC). We studied the explanted heart of a proband carrying the DSG2-N266S mutation as well as transgenic mice (Tg-NS) with cardiac overexpression of the mouse equivalent of this mutation, N271S-dsg2, with the aim of investigating the pathophysiological mechanisms involved. Transgenic mice recapitulated the clinical features of ARVC, including sudden death at young age, spontaneous ventricular arrhythmias, cardiac dysfunction, and biventricular dilatation and aneurysms. Investigation of transgenic lines with different levels of transgene expression attested to a dose-dependent dominant-negative effect of the mutation. We demonstrate for the first time that myocyte necrosis is the key initiator of myocardial injury, triggering progressive myocardial damage, including an inflammatory response and massive calcification within the myocardium, followed by injury repair with fibrous tissue replacement, and myocardial atrophy. These observations were supported by findings in the explanted heart from the patient. Insight into mechanisms initiating myocardial damage in ARVC is a prerequisite to the future development of new therapies aimed at delaying onset or progression of the disease.

The Cardiac Desmosome and Arrhythmogenic Cardiomyopathies

“…84 As in the case of desmoplakin, 83 overexpression of the wild-type gene did not yield a relevant phenotype. Transgenic mice with cardiac restricted expression of a desmoglein-2 gene containing mutation N271S recapitulated clinical features such as spontaneous ventricular arrhythmias and sudden death, cardiac dysfunction, biventricular dilatation and ventricular aneurysms.…”

“…[81][82][83][84] It is of interest to note that in all murine models of ARVC, transgenes have been cloned under the control of cardiac promoters; consequently, the role of noncardiac cells in the pathogenesis of the fibrofatty phenotype remains to be established. Murine models provide an opportunity to characterize, in the same animal population, the changes caused by one genetic modification on the morphology and function at various levels of organization, from the molecule to the living organism.…”

Arrhythmogenic Cardiomyopathy

“…Rather than being a continuous, ongoing process, disease progression may occur through periodic "acute bursts" of an otherwise stable disease, as to mimic myocarditis or myocardial infarction with normal coronary arteries. In a desmoglein-2 (dsg2) transgenic animal model, myocyte necrosis was demonstrated to be the key initiator of myocardial injury, triggering progressive myocardial damage, followed by an inflammatory response [21]. The detection of viral genomes let to advance an infective viral etiology, but it is most likely that either viruses are innocent bystanders or that myocardial cell degeneration may serve as a milieu favoring viral settlement [22].…”

Desmoglein 2–Dependent Arrhythmogenic Cardiomyopathy Is Caused by a Loss of Adhesive Function

“…18 Subsequently, mice were generated overexpressing murine mutant Dsg2 N271S corresponding to the pathogenic human Dsg2 N266S mutation. 11 The mutation is localized in the second extracellular calcium-binding pocket, presumably contributing to Dsg2's adhesive function. These mice developed, in contrast to mice overexpressing the same amount of Dsg2 WT, symptoms of AC, including biventricular dilation, calcifying necrosis with replacement fibrosis, conduction defects, and arrhythmia, occasionally resulting in premature death.…”

“…These mice developed, in contrast to mice overexpressing the same amount of Dsg2 WT, symptoms of AC, including biventricular dilation, calcifying necrosis with replacement fibrosis, conduction defects, and arrhythmia, occasionally resulting in premature death. 11 Later on, a knock-in mouse model was described producing mutant Dsg2 with a deletion in the extracellular domains EC1-EC2. Live-born homozygous DSG2 MT carriers developed an AC-like phenotype during adolescence.…”