Myocyte necrosis underlies progressive myocardial dystrophy in mouse dsg2-related arrhythmogenic right ventricular cardiomyopathy.
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.
Pilichou
Kalliopi
K
Department of Medical Diagnostic Sciences and Special Therapies, University of Padua, 35121 Padua, Italy.
Remme
Carol Ann
CA
Basso
Cristina
C
Campian
Maria E
ME
Rizzo
Stefania
S
Barnett
Phil
P
Scicluna
Brendon P
BP
Bauce
Barbara
B
van den Hoff
Maurice J B
MJ
de Bakker
Jacques M T
JM
Tan
Hanno L
HL
Valente
Marialuisa
M
Nava
Andrea
A
Wilde
Arthur A M
AA
Moorman
Antoon F M
AF
Thiene
Gaetano
G
Bezzina
Connie R
CR
D019943:Amino Acid Substitution; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000235:genetics*; D001483:Base Sequence; D009202:Cardiomyopathies / Q000235:genetics* / Q000473:pathology*; D017931:DNA Primers / Q000235:genetics; D051301:Desmoglein 2 / Q000235:genetics* / Q000502:physiology*; D004562:Electrocardiography; D005260:Female; D015870:Gene Expression; D006801:Humans; D066298:In Vitro Techniques; D051379:Mice; D008822:Mice, Transgenic; D008875:Middle Aged; D020125:Mutation, Missense; D032383:Myocytes, Cardiac / Q000473:pathology*; D009336:Necrosis; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D018497:Ventricular Dysfunction, Right / Q000235:genetics* / Q000473:pathology* / Q000503:physiopathology
D017931:DNA Primers; D051301:Desmoglein 2; C495315:Dsg2 protein, mouse; D011994:Recombinant Proteins