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Advances in Ion Channel, Non-Desmosomal Variants and Autophagic Mechanisms Implicated in Arrhythmogenic Cardiomyopathy.

ABSTRACT: Arrhythmogenic cardiomyopathy (ACM) is a heterogeneous disorder characterized by the replacement of cardiac myocytes with fibro-fatty tissues, leading to abnormal excitation-contraction (EC) coupling and a range of malignant events, such as ventricular tachycardia (VT), sudden cardiac death/arrest (SCD/A) and heart failure (HF). The concept of ACM has recently been ex-tended to include right ventricular cardiomyopathy (ARVC), left ventricular cardiomyopathy (ALVC) and biventricular cardiomyopathy. ARVC is generally seen as the most common type of ACM. The pathogenesis of ACM involves mutation variants in desmosomal or non-desmosomal gene loci, as well as various external factors, such as intense exercise, stress and infections. Ion channel alterations, autophagy and non-desmosomal variants are also important components in the development of ACM. As clinical practice enters the era of precision therapy, it is important to review recent studies on these topics to better diagnose and treat the molecular phase of ACM.

SUBMITTER: Li K

PROVIDER: S-EPMC10047275 | biostudies-literature | 2023 Mar

REPOSITORIES: biostudies-literature

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Advances in Ion Channel, Non-Desmosomal Variants and Autophagic Mechanisms Implicated in Arrhythmogenic Cardiomyopathy.

Li Kexin K Jiang Yufeng Y Zeng Yiyao Y Zhou Yafeng Y

Current issues in molecular biology 20230307 3

Arrhythmogenic cardiomyopathy (ACM) is a heterogeneous disorder characterized by the replacement of cardiac myocytes with fibro-fatty tissues, leading to abnormal excitation-contraction (EC) coupling and a range of malignant events, such as ventricular tachycardia (VT), sudden cardiac death/arrest (SCD/A) and heart failure (HF). The concept of ACM has recently been ex-tended to include right ventricular cardiomyopathy (ARVC), left ventricular cardiomyopathy (ALVC) and biventricular cardiomyopath ...[more]

PMID: 36975511

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Project description:BackgroundArrhythmogenic cardiomyopathy (ACM) is characterized by progressive loss of cardiomyocytes with fibrofatty tissue replacement, systolic dysfunction, and life-threatening arrhythmias. A substantial proportion of ACM is caused by mutations in genes of the desmosomal cell-cell adhesion complex, but the underlying mechanisms are not well understood. In the current study, we investigated the relevance of defective desmosomal adhesion for ACM development and progression.MethodsWe mutated the binding site of DSG2 (desmoglein-2), a crucial desmosomal adhesion molecule in cardiomyocytes. This DSG2-W2A mutation abrogates the tryptophan swap, a central interaction mechanism of DSG2 on the basis of structural data. Impaired adhesive function of DSG2-W2A was confirmed by cell-cell dissociation assays and force spectroscopy measurements by atomic force microscopy. The DSG2-W2A knock-in mouse model was analyzed by echocardiography, ECG, and histologic and biomolecular techniques including RNA sequencing and transmission electron and superresolution microscopy. The results were compared with ACM patient samples, and their relevance was confirmed in vivo and in cardiac slice cultures by inhibitor studies applying the small molecule EMD527040 or an inhibitory integrin-αVβ6 antibody.ResultsThe DSG2-W2A mutation impaired binding on molecular level and compromised intercellular adhesive function. Mice bearing this mutation develop a severe cardiac phenotype recalling the characteristics of ACM, including cardiac fibrosis, impaired systolic function, and arrhythmia. A comparison of the transcriptome of mutant mice with ACM patient data suggested deregulated integrin-αVβ6 and subsequent transforming growth factor-β signaling as driver of cardiac fibrosis. Blocking integrin-αVβ6 led to reduced expression of profibrotic markers and reduced fibrosis formation in mutant animals in vivo.ConclusionsWe show that disruption of desmosomal adhesion is sufficient to induce a phenotype that fulfils the clinical criteria to establish the diagnosis of ACM, confirming the dysfunctional adhesion hypothesis. Deregulation of integrin-αVβ6 and transforming growth factor-β signaling was identified as a central step toward fibrosis. A pilot in vivo drug test revealed this pathway as a promising target to ameliorate fibrosis. This highlights the value of this model to discern mechanisms of cardiac fibrosis and to identify and test novel treatment options for ACM.

Project description:BackgroundImmunoreactive signal for the desmosomal protein plakoglobin (γ-catenin) is reduced at cardiac intercalated disks in patients with arrhythmogenic right ventricular cardiomyopathy (ARVC), a highly arrhythmogenic condition caused by mutations in genes encoding desmosomal proteins. Previously, we observed a false-positive case in which plakoglobin signal was reduced in a patient initially believed to have ARVC but who actually had cardiac sarcoidosis. Sarcoidosis can masquerade clinically as ARVC but has not been previously associated with altered desmosomal proteins.Methods and resultsWe observed marked reduction in immunoreactive signal for plakoglobin at cardiac myocyte junctions in patients with sarcoidosis and giant cell myocarditis, both highly arrhythmogenic forms of myocarditis associated with granulomatous inflammation. In contrast, plakoglobin signal was not depressed in lymphocytic (nongranulomatous) myocarditis. To determine whether cytokines might promote dislocation of plakoglobin from desmosomes, we incubated cultures of neonatal rat ventricular myocytes with selected inflammatory mediators. Brief exposure to low concentrations of interleukin (IL)-17, tumor necrosis factor-α (TNF-α), and IL-6 (cytokines implicated in granulomatous myocarditis) caused translocation of plakoglobin from cell-cell junctions to intracellular sites, whereas other potent cytokines implicated in nongranulomatous myocarditis had no effect, even at much higher concentrations. We also observed myocardial expression of IL-17 and TNF-α and elevated levels of serum inflammatory mediators, including IL-6R, IL-8, monocyte chemoattractant protein 1, and macrophage inflammatory protein 1β, in patients with ARVC (all P<0.0001 compared with controls).ConclusionsThe results suggest novel disease mechanisms involving desmosomal proteins in granulomatous myocarditis and implicate cytokines, perhaps derived in part from the myocardium, in disruption of desmosomal proteins and arrhythmogenesis in ARVC.

Dataset Information

Advances in Ion Channel, Non-Desmosomal Variants and Autophagic Mechanisms Implicated in Arrhythmogenic Cardiomyopathy.

Publications

Advances in Ion Channel, Non-Desmosomal Variants and Autophagic Mechanisms Implicated in Arrhythmogenic Cardiomyopathy.

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