INVESTIGADORES
GARCIA GRAS Eduardo Andres
artículos
Título:
Suppression of canonical Wnt/beta-catenin signaling by nuclear plakoglobin recapitulates phenotype of arrhythmogenic right ventricular cardiomyopathy
Autor/es:
EDUARDO GARCIA-GRAS; LOMBARDI, RAFFAELLA; GIOCONDO, MICHAEL J; WILLERSON, JAMES T; SCHNEIDER, MICHAEL D; KHOURY, DIRAR S; MARIAN, ALI J
Revista:
JOURNAL OF CLINICAL INVESTIGATION
Editorial:
AMER SOC CLINICAL INVESTIGATION INC
Referencias:
Lugar: Ann Arbor, Michigan; Año: 2006 vol. 116 p. 1825 - 1828
ISSN:
0021-9738
Resumen:
Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVC) is a genetic
disease caused by mutations in desmosomal proteins. The phenotypic hallmark of
ARVC is fibroadipocytic replacement of cardiac myocytes, which is a unique
phenotype with a yet-to-be-defined molecular mechanism. We established atrial
myocyte cell lines expressing siRNA against desmoplakin (DP), responsible for
human ARVC. We show suppression of DP expression leads to nuclear localization of
the desmosomal protein plakoglobin and a 2-fold reduction in canonical
Wnt/beta-catenin signaling through Tcf/Lef1 transcription factors. The ensuing
phenotype is increased expression of adipogenic and fibrogenic genes and
accumulation of fat droplets. We further show that cardiac-restricted deletion of
Dsp, encoding DP, impairs cardiac morphogenesis and leads to high embryonic
lethality in the homozygous state. Heterozygous DP-deficient mice exhibited
excess adipocytes and fibrosis in the myocardium, increased myocyte apoptosis,
cardiac dysfunction, and ventricular arrhythmias, thus recapitulating the
phenotype of human ARVC. We believe our results provide for a novel molecular
mechanism for the pathogenesis of ARVC and establish cardiac-restricted
DP-deficient mice as a model for human ARVC. These findings could provide for the
opportunity to identify new diagnostic markers and therapeutic targets in
patients with ARVC.