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Intracellular calcium current disorder and disease phenotype in OBSCN mutant iPSC-based cardiomyocytes in arrhythmogenic right ventricular cardiomyopathy.

ABSTRACT: Obscurin participates in the development of striated muscles and maintenance of the functional sarcoplasmic reticulum. However, the role of obscurin in arrhythmogenic right ventricular cardiomyopathy (ARVC) is not well understood. We aimed to study the novel obscurin mutations in the pathogenesis of ARVC and the underlying mechanisms. Methods: We generated induced pluripotent stem cells (iPSC) through retroviral reprogramming of peripheral blood mononuclear cells isolated from a 46-year-old female diagnosed with ARVC, carrying a mutation in OBSCN. The cells differentiated into functional iPSC-based cardiomyocytes (iPSC-CMs), whose phenotype was determined by transmission electron microscopy, electrophysiological description, immunofluorescence staining, and Oil Red O staining. Molecular characterization was performed by bioinformatic analyses, and identification by quantitative real-time polymerase chain reaction (qRT-PCR) and Western blotting. Results: ARVC-iPSC-CMs mutation in OBSCN showed significant accumulation of lipids, increased pleomorphism, irregular Z-bands, and increased L type calcium currents. Functional enrichment analysis identified pathways involved in focal adhesion and structure formation; the adipocytokines and PPAR signaling pathways were also activated in the ARVC group. Moreover, our results from ultra-high-resolution microscopy, qRT-PCR and Western blotting confirmed that the mutant OBSCN protein and its anchor protein, Ank1.5, showed structural disorder and decreased expression, but there was increased expression of junctional protein N-Cadherin. Further analysis revealed the gene expression of other desmosomal proteins in ARVC-iPSC-CMs was also decreased but some adipogenesis pathway-related proteins (PPAR?, C/EBP?, and FABP4) were increased. Conclusion: A novel frameshift mutation in OBSCN caused phenotypic alteration accompanied by disrupted localization and decreased expression of its anchoring protein Ank1.5. Furthermore, there was an accumulation of lipids with an increase in fatty fibrosis area and myocardial structural disorder, possibly leading to dysrhythmia in calcium channel-related myocardial contraction. These observations suggested the possibility of attenuating ARVC progression by therapeutic modulation of OBSCN expression.

SUBMITTER: Chen P

PROVIDER: S-EPMC7532677 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Intracellular calcium current disorder and disease phenotype in <i>OBSCN</i> mutant iPSC-based cardiomyocytes in arrhythmogenic right ventricular cardiomyopathy.

Chen Peipei P Xiao Ying Y Wang Yuanpin Y Zheng Zhifa Z Chen Lianfeng L Yang Xufei X Li Jingyi J Wu Wei W Zhang Shuyang S

Theranostics 20200914 24

Obscurin participates in the development of striated muscles and maintenance of the functional sarcoplasmic reticulum. However, the role of obscurin in arrhythmogenic right ventricular cardiomyopathy (ARVC) is not well understood. We aimed to study the novel obscurin mutations in the pathogenesis of ARVC and the underlying mechanisms. <b>Methods:</b> We generated induced pluripotent stem cells (iPSC) through retroviral reprogramming of peripheral blood mononuclear cells isolated from a 46-year-o ...[more]

PMID: 33042279

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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

Intracellular calcium current disorder and disease phenotype in OBSCN mutant iPSC-based cardiomyocytes in arrhythmogenic right ventricular cardiomyopathy.

Publications

Intracellular calcium current disorder and disease phenotype in <i>OBSCN</i> mutant iPSC-based cardiomyocytes in arrhythmogenic right ventricular cardiomyopathy.

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