2026-05-17T00:18:39Zhttps://repisalud.isciii.es/rest/oai/requestoai:repisalud.isciii.es:20.500.12105/85232024-10-31T11:44:32Zcom_20.500.12105_19604com_20.500.12105_2051col_20.500.12105_19605col_20.500.12105_19607
Repisalud
author
Padron-Barthe, Laura
author
Villalba-Orero, Maria
author
Gomez-Salinero, Jesus M.
author
Dominguez, Fernando
author
Román, Marta
author
Larrasa-Alonso, Javier
author
Ortiz-Sanchez, Paula
author
Martinez, Fernando
author
Lopez-Olaneta, Marina
author
Bonzon-Kulichenko, Elena
author
Vazquez, Jesus
author
Marti-Gomez, Carlos
author
Santiago, Demetrio J
author
Prados, Belen
author
Giovinazzo, Giovanna
author
Gómez-Gaviro, María Victoria
author
Priori, Silvia G.
author
Garcia-Pavia, Pablo
author
Lara-Pezzi, Enrique
funder
European Commission
funder
Ministerio de Economía y Competitividad (España)
funder
Instituto de Salud Carlos III
funder
Comunidad de Madrid (España)
funder
Fundación Isabel Gemio
funder
Sociedad Española de Cardiología
funder
Ministerio de Ciencia, Innovación y Universidades (España)
funder
Unión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF)
funder
Fundación ProCNIC
2019-10-22T13:57:44Z
2019-10-22T13:57:44Z
2019-10
Circulation. 2019; 140(14):1188-1204
10.1161/CIRCULATIONAHA.119.040366
1524-4539
0009-7322
Circulation
31567019
http://hdl.handle.net/20.500.12105/8523
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.
eng
GSK3β
TMEM43
arrhythmogenic right ventricular
calcineurin
dysplasia
therapy
Severe Cardiac Dysfunction and Death Caused by Arrhythmogenic Right Ventricular Cardiomyopathy Type 5 Are Improved by Inhibition of Glycogen Synthase Kinase-3β
journal article
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