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Severe Cardiac Dysfunction and Death Caused by Arrhythmogenic Right Ventricular Cardiomyopathy Type 5 Are Improved by Inhibition of Glycogen Synthase Kinase-3?.

ABSTRACT: 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 ?-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 ?-actin. TMEM43-S358L shows partial delocalization to the cytoplasm, reduced interaction with emerin and ?-actin, and activation of glycogen synthase kinase-3? (GSK3?). Furthermore, we show that targeting cardiac fibrosis has no beneficial effect, whereas overexpression of the calcineurin splice variant calcineurin A?1 results in GSK3? inhibition and improved cardiac function and survival. Similarly, treatment of TMEM43 mutant mice with a GSK3? inhibitor improves cardiac function. Finally, human induced pluripotent stem cells bearing the p.S358L mutation also showed contractile dysfunction that was partially restored after GSK3? inhibition. CONCLUSIONS:Our data provide evidence that TMEM43-S358L leads to sustained cardiomyocyte death and fibrofatty replacement. Overexpression of calcineurin A?1 in TMEM43 mutant mice or chemical GSK3? inhibition improves cardiac function and increases mice life span. Our results pave the way toward new therapeutic approaches for ARVC5.

SUBMITTER: Padron-Barthe L

PROVIDER: S-EPMC6784777 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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Severe Cardiac Dysfunction and Death Caused by Arrhythmogenic Right Ventricular Cardiomyopathy Type 5 Are Improved by Inhibition of Glycogen Synthase Kinase-3β.

Padrón-Barthe Laura L Villalba-Orero María M Gómez-Salinero Jesús M JM Domínguez Fernando F Román Marta M Larrasa-Alonso Javier J Ortiz-Sánchez Paula P Martínez Fernando F López-Olañeta Marina M Bonzón-Kulichenko Elena E Vázquez Jesús J Martí-Gómez Carlos C Santiago Demetrio J DJ Prados Belén B Giovinazzo Giovanna G Gómez-Gaviro María Victoria MV Priori Silvia S Garcia-Pavia Pablo P Lara-Pezzi Enrique E

Circulation 20190905 14

<h4>Background</h4>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 muta ...[more]

PMID: 31567019

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Project description:Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited cardiomyopathy characterized by ventricular arrhythmias and an increased risk of sudden cardiac death. Although structural abnormalities of the right ventricle predominate, it is well recognized that left ventricular involvement is common, particularly in advanced disease, and that left-dominant forms occur. The pathological characteristic of ARVC is myocyte loss with fibrofatty replacement. Since the first detailed clinical description of the disorder in 1982, significant advances have been made in understanding this disease. Once the diagnosis of ARVC is established, the single most important clinical decision is whether a particular patient's sudden cardiac death risk is sufficient to justify placement of an implantable cardioverter-defibrillator. The importance of this decision reflects the fact that ARVC is a common cause of sudden death in young people and that sudden death may be the first manifestation of the disease. This decision is particularly important because these are often young patients who are expected to live for many years. Although an implantable cardioverter-defibrillator can save lives in individuals with this disease, it is also well recognized that implantable cardioverter-defibrillator therapy is associated with both short- and long-term complications. Decisions about the placement of an implantable cardioverter-defibrillator are based on an estimate of a patient's risk of sudden cardiac death, as well as their preferences and values. The primary purpose of this article is to provide a review of the literature that concerns risk stratification in patients with ARVC and to place this literature in the framework of the 3 authors' considerable lifetime experiences in caring for patients with ARVC. The most important parameters to consider when determining arrhythmic risk include electric instability, including the frequency of premature ventricular contractions and sustained ventricular arrhythmia; proband status; extent of structural disease; cardiac syncope; male sex; the presence of multiple mutations or a mutation in TMEM43; and the patient's willingness to restrict exercise and to eliminate participation in competitive or endurance exercise.

Dataset Information

Severe Cardiac Dysfunction and Death Caused by Arrhythmogenic Right Ventricular Cardiomyopathy Type 5 Are Improved by Inhibition of Glycogen Synthase Kinase-3?.

Publications

Severe Cardiac Dysfunction and Death Caused by Arrhythmogenic Right Ventricular Cardiomyopathy Type 5 Are Improved by Inhibition of Glycogen Synthase Kinase-3β.

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