Elucidation of the pathology in ARVC caused by Japanese-specific DSG2 mutations using knock-in mice models: searching for the therapeutic targets

• Project/Area Number: 21K08119
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 53020:Cardiology-related
• Research Institution: National Cardiovascular Center Research Institute
• Principal Investigator: ZANKOV DimitarP 国立研究開発法人国立循環器病研究センター, オープンイノベーションセンター, 室長 (20631295)
• Co-Investigator(Kenkyū-buntansha): 大野 聖子 国立研究開発法人国立循環器病研究センター, 研究所, 部長 (20610025)
• Project Period (FY): 2021-04-01 – 2024-03-31
• Project Status: Completed (Fiscal Year 2023)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2023: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2022: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2021: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: ARVC / DSG2 / Mouse model / Cardiomyopathy / Arrhythmia / Desmosome / Desmoglein 2

Outline of Research at the Start

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).

Outline of Annual Research Achievements

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.

Research Products

• [Journal Article] RhoA rescues cardiac senescence by regulating Parkin-mediated mitophagy (2023)
  • Author(s): Soh Joanne Ern Chi、Shimizu Akio、Molla Md Rasel、Zankov Dimitar P.、Nguyen Le Kim Chi、Khan Mahbubur Rahman、Tesega Wondwossen Wale、Chen Si、Tojo Misa、Ito Yoshito、Sato Akira、Hitosugi Masahito、Miyagawa Shigeru、Ogita Hisakazu
  • Journal Title: Journal of Biological Chemistry Volume: 299 Issue: 3 Pages: 102993-102993
  • DOI: 10.1016/j.jbc.2023.102993
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Identification of transmembrane protein 168 mutation in familial Brugada syndrome. (2020)
  • Author(s): Shimizu A, Zankov DP, Sato A, Komeno M, Toyoda F, Yamazaki S, Makita T, Noda T, Ikawa M, Asano Y, Miyashita Y, Takashima S, Morita H, Ishikawa T, Makita N, Hitosugi M, Matsuura H, Ohno S, Horie M, Ogita H.
  • Journal Title: FASEB Journal Volume: 34 Issue: 5 Pages: 6399-6417
  • DOI: 10.1096/fj.201902991r
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] Gain-of-Function KCND3 Variants Identified in Young Patients with Refractory Epilepsy might be a Cause of Sudden Unexpected Death in Epilepsy. (2023)
  • Author(s): Byambajav Tserenlkham, Koichiro Takayama, Dimitar Zankov, Minoru Horie, Seiko Ohno
  • Organizer: Heart Rhythm Soceity Meeting 2023
  • Int'l Joint Research
• [Presentation] Human-specific desmoglein 2 mutations in mice models of arrhythmogenic right ventricular cardiomyopathy reproduce patients' phenotype (2021)
  • Author(s): Zankov Dimitar
  • Organizer: Europeean Heart Rhythm Association
  • Int'l Joint Research