RT Journal Article
T1 Severe Cardiac Dysfunction and Death Caused by Arrhythmogenic Right Ventricular Cardiomyopathy Type 5 Are Improved by Inhibition of Glycogen Synthase Kinase-3β
A1 Padrón-Barthe, Laura
A1 Gómez-Salinero, Jesús M.
A1 Domínguez, Fernando
A1 Román, Marta
A1 Larrasa-Alonso, Javier
A1 Martínez, Fernando
A1 López-Olañeta, Marina
A1 Bonzón-Kulichenko, Elena
A1 Vázquez, Jesús
A1 Martí-Gómez, Carlos
A1 Santiago, Demetrio J.
A1 Prados, Belén
A1 Giovinazzo, Giovanna
A1 Gómez-Gaviro, María Victoria
A1 Priori, Silvia
A1 Garcia-Pavia, Pablo
A1 Lara-Pezzi, Enrique
A1 Villalba Orero, María
A1 Ortiz Sánchez, Paula
AB BACKGROUND: Arrhythmogenic cardiomyopathy/arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited cardiac disease characterized by fibrofatty replacement of the myocardium, resulting in heart failure and sudden cardiac death. The most aggressive arrhythmogenic cardiomyopathy/ARVC subtype is ARVC type 5 (ARVC5), caused by a p.S358L mutation in TMEM43 (transmembrane protein 43). The function and localization of TMEM43 are unknown, as is the mechanism by which the p.S358L mutation causes the disease. Here, we report the characterization of the first transgenic mouse model of ARVC5. METHODS: We generated transgenic mice overexpressing TMEM43 in either its wild-type or p.S358L mutant (TMEM43-S358L) form in postnatal cardiomyocytes under the control of the α-myosin heavy chain promoter. RESULTS: We found that mice expressing TMEM43-S358L recapitulate the human disease and die at a young age. Mutant TMEM43 causes cardiomyocyte death and severe fibrofatty replacement. We also demonstrate that TMEM43 localizes at the nuclear membrane and interacts with emerin and β-actin. TMEM43-S358L shows partial delocalization to the cytoplasm, reduced interaction with emerin and β-actin, and activation of glycogen synthase kinase-3β (GSK3β). Furthermore, we show that targeting cardiac fibrosis has no beneficial effect, whereas overexpression of the calcineurin splice variant calcineurin Aβ1 results in GSK3β inhibition and improved cardiac function and survival. Similarly, treatment of TMEM43 mutant mice with a GSK3β inhibitor improves cardiac function. Finally, human induced pluripotent stem cells bearing the p.S358L mutation also showed contractile dysfunction that was partially restored after GSK3β inhibition. CONCLUSIONS: Our data provide evidence that TMEM43-S358L leads to sustained cardiomyocyte death and fibrofatty replacement. Overexpression of calcineurin Aβ1 in TMEM43 mutant mice or chemical GSK3β inhibition improves cardiac function and increases mice life span. Our results pave the way toward new therapeutic approaches for ARVC5.
PB American Heart Association
SN 0009-7322
SN 1524-4539
YR 2019
FD 2019-10-01
LK https://hdl.handle.net/20.500.14352/95164
UL https://hdl.handle.net/20.500.14352/95164
LA eng
NO Unión Europea
NO Ministerio de Economía y Competitividad
NO Instituto de Salud Carlos III
NO Comunidad de Madrid
NO Fundación Isabel Gemio
NO Sociedad Española de cardiología
NO European Regional Development Fund (FEDER)
NO Centro Nacional de Investigaciones Cardiovasculares Carlos III
NO Centro Severo Ochoa de Excelencia
DS Docta Complutense
RD 12 abr 2025