1. Academic Validation
  2. Decreased Expression of Plakophilin-2 and αT-Catenin in Arrhythmogenic Right Ventricular Cardiomyopathy: Potential Markers for Diagnosis

Decreased Expression of Plakophilin-2 and αT-Catenin in Arrhythmogenic Right Ventricular Cardiomyopathy: Potential Markers for Diagnosis

  • Int J Mol Sci. 2022 May 16;23(10):5529. doi: 10.3390/ijms23105529.
Pei-Fang Hung 1 Fa-Po Chung 1 2 Chung-Lieh Hung 3 4 5 Yenn-Jiang Lin 1 2 Tzu-Ting Kuo 2 6 Jo-Nan Liao 1 2 Yun-Yu Chen 1 7 Chih-Hsin Pan 8 Kai-Ping Shaw 8 Shih-Ann Chen 1 2
Affiliations

Affiliations

  • 1 Heart Rhythm Center and Division of Cardiology, Department of Medicine, Taipei Veterans General Hospital, Taipei 112201, Taiwan.
  • 2 Institute of Clinical Medicine and Cardiovascular Research Center, National Yang Ming Chiao Tung University, Taipei 112304, Taiwan.
  • 3 Department of Medicine, Mackay Medical College, New Taipei City 252005, Taiwan.
  • 4 Institute of Biomedical Sciences, Mackay Medical College, New Taipei City 252005, Taiwan.
  • 5 Division of Cardiology, Department of Internal Medicine, Mackay Memorial Hospital, Taipei 104217, Taiwan.
  • 6 Division of Cardiovascular Surgery, Department of Surgery, Taipei Veterans General Hospital, Taipei 112201, Taiwan.
  • 7 Institute of Epidemiology and Preventive Medicine College of Public Health, National Taiwan University, Taipei 100025, Taiwan.
  • 8 Institute of Forensic Medicine, Ministry of Justice, New Taipei City 235016, Taiwan.
Abstract

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a hereditary disease of the heart muscle. Clinical challenges remain, however, in identifying patients with ARVC in the early or concealed stages with subtle clinical manifestations. Therefore, we wanted to identify potential targets by immunohistochemical (IHC) analysis in comparison with controls. Pathogenic mutations were identified in 11 of 37 autopsied patients with ARVC. As observed from IHC analysis of the RV, expression of αT-catenin and plakophilin-2 is significantly decreased in autopsied patients with ARVC as compared to controls, and the decreased expression is consistent in patients with and without pathogenic mutations. Furthermore, ARVC specimens demonstrated a reduced localization of αT-catenin, Desmocollin-2, desmoglein-2, desmoplakin, and plakophilin-2 on intercalated discs. These findings have been validated by comparing RV specimens obtained via endomyocardial biopsy between patients with ARVC and those without. The pathogenic mutation was present in 3 of 5 clinical patients with ARVC. In HL-1 myocytes, siRNA was used to knockdown CTNNA3, and western blotting analysis demonstrated that the decline in αT-catenin expression was accompanied by a significant decline in the expression of plakophilin-2. The aforementioned effect was directed towards protein degradation rather than mRNA stability. Plakophilin-2 expression decreases concurrently with the decline in CTNNA3 expression. Therefore, the expression of αT-catenin and plakophilin-2 could be potential surrogates for the diagnosis of ARVC.

Keywords

CTNNA3; arrhythmogenic right ventricular cardiomyopathy; immunohistochemistry staining; plakophilin-2; αT-catenin.

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