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Patient-specific iPSC-derived cardiomyocytes reveal aberrant activation of Wnt/ß-catenin signaling in SCN5A-related Brugada syndrome.
Cai, Dongsheng; Wang, Xiaochen; Sun, Yaxun; Fan, Hangping; Zhou, Jingjun; Yang, Zongkuai; Qiu, Hangyuan; Wang, Jue; Su, Jun; Gong, Tingyu; Jiang, Chenyang; Liang, Ping.
Afiliação
  • Cai D; Department of Cardiology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, 3 Qingchun East Road, Hangzhou, 310016, China.
  • Wang X; Key Laboratory of Combined Multi-Organ Transplantation, Ministry of Public Health, the First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Road, Hangzhou, 310003, China.
  • Sun Y; Institute of Translational Medicine, Zhejiang University, Hangzhou, 310029, China.
  • Fan H; Department of Cardiology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, 3 Qingchun East Road, Hangzhou, 310016, China.
  • Zhou J; Key Laboratory of Combined Multi-Organ Transplantation, Ministry of Public Health, the First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Road, Hangzhou, 310003, China.
  • Yang Z; Institute of Translational Medicine, Zhejiang University, Hangzhou, 310029, China.
  • Qiu H; Key Laboratory of Combined Multi-Organ Transplantation, Ministry of Public Health, the First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Road, Hangzhou, 310003, China.
  • Wang J; Institute of Translational Medicine, Zhejiang University, Hangzhou, 310029, China.
  • Su J; Key Laboratory of Combined Multi-Organ Transplantation, Ministry of Public Health, the First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Road, Hangzhou, 310003, China.
  • Gong T; Institute of Translational Medicine, Zhejiang University, Hangzhou, 310029, China.
  • Jiang C; Department of Cardiology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, 3 Qingchun East Road, Hangzhou, 310016, China.
  • Liang P; Key Laboratory of Combined Multi-Organ Transplantation, Ministry of Public Health, the First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Road, Hangzhou, 310003, China.
Stem Cell Res Ther ; 14(1): 241, 2023 09 08.
Article em En | MEDLINE | ID: mdl-37679791
BACKGROUND: Mutations in the cardiac sodium channel gene SCN5A cause Brugada syndrome (BrS), an arrhythmic disorder that is a leading cause of sudden death and lacks effective treatment. An association between SCN5A and Wnt/ß-catenin signaling has been recently established. However, the role of Wnt/ß-catenin signaling in BrS and underlying mechanisms remains unknown. METHODS: Three healthy control subjects and one BrS patient carrying a novel frameshift mutation (T1788fs) in the SCN5A gene were recruited in this study. Control and BrS patient-specific induced pluripotent stem cells (iPSCs) were generated from skin fibroblasts using nonintegrated Sendai virus. All iPSCs were differentiated into cardiomyocytes using monolayer-based differentiation protocol. Action potentials and sodium currents were recorded from control and BrS iPSC-derived cardiomyocytes (iPSC-CMs) by single-cell patch clamp. RESULTS: BrS iPSC-CMs exhibited increased burden of arrhythmias and abnormal action potential profile featured by slower depolarization, decreased action potential amplitude, and increased beating interval variation. Moreover, BrS iPSC-CMs showed cardiac sodium channel (Nav1.5) loss-of-function as compared to control iPSC-CMs. Interestingly, the electrophysiological abnormalities and Nav1.5 loss-of-function observed in BrS iPSC-CMs were accompanied by aberrant activation of Wnt/ß-catenin signaling. Notably, inhibition of Wnt/ß-catenin significantly rescued Nav1.5 defects and arrhythmic phenotype in BrS iPSC-CMs. Mechanistically, SCN5A-encoded Nav1.5 interacts with ß-catenin, and reduced expression of Nav1.5 leads to re-localization of ß-catenin in BrS iPSC-CMs, which aberrantly activates Wnt/ß-catenin signaling to suppress SCN5A transcription. CONCLUSIONS: Our findings suggest that aberrant activation of Wnt/ß-catenin signaling contributes to the pathogenesis of SCN5A-related BrS and point to Wnt/ß-catenin as a potential therapeutic target.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Síndrome de Brugada / Células-Tronco Pluripotentes Induzidas Tipo de estudo: Guideline Limite: Humans Idioma: En Revista: Stem Cell Res Ther Ano de publicação: 2023 Tipo de documento: Article País de afiliação: China

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Síndrome de Brugada / Células-Tronco Pluripotentes Induzidas Tipo de estudo: Guideline Limite: Humans Idioma: En Revista: Stem Cell Res Ther Ano de publicação: 2023 Tipo de documento: Article País de afiliação: China