| 研究開始時の研究の概要 |
Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC) is an inherited disease, which
progresses to terminal heart failure and may cause sudden cardiac death. Causative mutations affect mainly desmosomal proteins in the intercalated disks. So far, there is no curative therapy for ARVC. We generated knock-in mice carrying the most common mutations among Japanese ARVC patients: DSG2 p.R292C and p.D494A. We perform in vivo and in vitro experiments to characterize the phenotype and detect specific signaling underlying pathology in ARVC. Our purpose is to identify a possible therapeutic target(s).
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| 研究実績の概要 |
There are two DSG2 founder variants in Japanese ARVC, p.R292C and p.D494A. In human, most patients carry the variants in homozygous or compound heterozygous manner. Compared to RYR2 variant carriers, DSG2 variant carries show early onset of heart failure and less ventricular arrhythmia. To elucidate the mechanism of ARVC caused by DSG2 variants, we constructed knock-in (KI) mice model with corresponding these variants, dsg2 R297C and D499A. The survival of homozygous R297C mice was worse than homozygous D499A, heterozygous KI ones and WT. In the echo cardiography and cardiac MRI, we could confirm the enlargement of both ventricles and left ventricular dysfunction in KI mice, especially with homozygous variants. Exercise stress training except for homozygous R297C exacerbated cardiac function and enlarged the cavities in mice models, which represents the human phenotype frequently observed in athletes. In the histological analysis, we found severe fibrosis, especially in the right ventricular wall. To access the cause of severe cardiac dysfunction, we evaluated the apoptosis of cardiomyocytes and found that apoptosis was significant in cardiomyocytes in homozygous KI mice. In the telemetry analysis, we could find atrio-ventricular block, however, the ventricular arrhythmias were rare.
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