Unravelling the insulin pathway of arrhythmogenic right ventricular cardiomyopathy (ARVC)
Clinical and pathological features of ARVC Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a hereditary disorder of the cardiac muscle characterised by ventricular arrhythmias, cardiac failure and sudden cardiac death (Basso et al., 2009; Thiene et al., 1988). Indeed, sudden cardiac deat...
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| Định dạng: | Journal article |
| Ngôn ngữ: | English |
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2022
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| Truy cập trực tuyến: | http://scholar.dlu.edu.vn/handle/123456789/1576 |
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| Thư viện lưu trữ: | Thư viện Trường Đại học Đà Lạt |
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| Tóm tắt: | Clinical and pathological features of ARVC
Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a hereditary disorder of the cardiac muscle characterised by ventricular arrhythmias, cardiac failure and sudden cardiac death (Basso et al., 2009; Thiene et al., 1988). Indeed, sudden cardiac death is the first presentation of ARVC in up to 70% of probands. Inherited in a Mendelian fashion, ARVC characteristically displays autosomal dominant transmission with variable age and sex-related penetrance (Sen-Chowdhry et al., 2005), although recessive forms exist in conjunction with abnormalities of skin and hair, the cardiocutaneous syndromes (McKoy et al., 2000; Norgett et al., 2000a). Variations in phenotypic expression include an initial phase of ARVC, where younger patients may display intermittent exacerbations of disease activity responsible for life-threatening ventricular arrhythmias, in an otherwise dormant process (Corrado et al., 1990), and increasing evidence of a myocardial process beyond just the right ventricular inlet, apex and outflow tract. The genetic and cellular mechanisms behind the marked heterogeneity of disease expression in this unique phenotype still remain unclear.
Genetic and cellular basis of ARVC
The association of ARVC with cutaneous and hair follicle abnormalities (cardiocutaneous syndromes) in large or multiple kindreds with autosomal recessive inheritance, led to the identification of the desmosome as critical to disease pathogenesis. Desmosomes are intercellular junctions of both epithelial and cardiovascular tissues that connect intermediate filaments (IFs) of adjacent cells, generating a large and mechanically resilient network. Simultaneous reports in 2000 described mutations in the desmosomal proteins Desmoplakin (DP) by the Kelsell group (Norgett et al., 2000b) leading to Cavajal syndrome, and Plakoglobin (Pg) by the McKenna group leading to Naxos disease (McKoy et al., 2000; Rampazzo et al., 2002). Myocardial fibrofatty infiltration is present in both syndromes, although there were marked differences in cardiac phenotype; classical ARVC in Naxos disease and left ventricular arrhythmogenic cardiomyopathy in Cavajal syndrome. Subsequently, mutations in all five classes of desmosomal proteins have been associated with autosomal dominant ARVC (Alcalai et al., 2003; Bauce et al., 2010; Gerull et al., 2004; Lazzarini et al., 2015; Norgett et al., 2000b). One striking finding was that distinct mutations in the same gene can produce an array of phenotypes. For example, different DP mutations can lead to both cutaneous (skin fragility syndromes and a spectrum of palmoplantar keratodermas: PPKs) and/or cardiac (arrhythmogenic and dilated cardiomyopathies) conditions, although phenotypic expression and clinical severity vary widely (Lazzarini et al., 2015). Recently, our group in Korea University, Prof Young-Gyu Ko’s team has screened a large series of ARVC families for known cardiomyopathy genes and identified, Mitsugumin 53 (MG53) negatively regulates skeletal myogenesis by targeting insulin receptor substrate 1 (IRS-1) (Nguyen Thi Huynh Nga, published in Nature Cummunications July 2013) (Yi et al., 2013). There are novel mutations (unpublished data) that is a key point driver for this disease. Our research proposal will focus largely on the array of DP mutations identified from Dr Bui Chi Bao’s group (University of Medicine Hochiminh city) as DP is highly expressed in both skin and the heart in Viet Nam. In addition, we have access to DP mouse models and human gene constructs from the group of Korea University.
Disease Pathogenesis
At the pathological level, classical ARVC is characterised by right ventricular myocyte loss and fibrofatty replacement. Whilst traditionally affecting the right ventricle, biventricular and left ventricular forms are increasingly recognised particularly in disease due to desmoplakin mutations. There have been substantial efforts to understand the pathophysiological basis of the structural disease with a number of mechanisms proposed. The sub-clinical “concealed phase” of the disease without prominent pathological features is a major diagnostic and management challenge because of the early occurrence of arrhythmias and sudden death that appears out of proportion to the extent of macro and microscopic structural change. It also points to the possibility that the desmosome, in addition to endowing mechanical stability to the cardiac tissue network, also has effects on cellular excitability. Emerging evidence demonstrates that interactions may occur between the desmosome and connexins (Cx), predominantly Cx43 in the ventricle, and ion channels such as the sodium channel Nav1.5. The expression and subcellular distribution of both may be disturbed in ARVC influencing cellular excitability and promoting conduction heterogeneities. As the cellular mechanisms behind the marked heterogeneity of disease expression in ARVC largely remain unclear, our hypothesis is that increased biomechanical stress and/or inflammation underlie the severity of phenotype. The investigations proposed in this application will use ARVC desmosomal-associated mutations (with a focus on those affecting DP) combined with cell and animal models to dissect the cellular pathways and external stressors that underlie the spontaneous arrhythmias and cardiac deaths. Specifically, we propose to investigate mechanisms by which desmosomal associated proteins and pathways that regulate intercellular communication and cellular excitability contribute to disease pathogenesis.
Desmoplakin (DP) and ARVC
DP is the major component of the desmosome and a key linker plakin protein providing attachment for intermediate filaments (Fuchs and Cleveland, 1998; Kalluri and Neilson, 2003). Two major splice variants of DP exist, DPI and DPII. They are expressed at nearly equivalent levels in stratified epithelia such as the epidermis, but DPI is the predominant isoform in the heart (Fuchs and Cleveland, 1998; Gumbiner et al., 1988). We have shown, utilising both patient and in vitro data, that DPII is particularly important for desmosomal adhesion in the epidermis (Kalluri and Neilson, 2003). The structure of DP is shown in Figure 1A and shows the remarkable clustering of missense mutations in the N-terminal domain (this domain is common to both DP isoforms). There is no clear genotype-phenotype association but the N-terminus does appear to be a “hot-spot” for pathogenic ARVC mutations. Though the rod domain allows for homodimerization and the C-terminus mediates intermediate filament tethering, the N-terminus interacts with other desmosomal proteins. This suggests that the distinct disease-associated DP mutations in the N-terminus may affect protein interactions differentially. The exact residues necessary for DP to bind other desmosomal proteins are unknown, but studies have shown that constructs lacking the first 194 residues of DP lose border localization (Alcalai et al., 2003; Norgett et al., 2000b; Rampazzo et al., 2002). These findings suggest that the majority of the DP N-terminus (series of spectrin repeats with an SH3 loop) may have functions other than targeting DP to desmosomes.
Environmental and molecular “stressors” in ARVC
Though ARVC is a genetic disease inherited primarily as an autosomal dominant trait, its disease expressivity (penetrance) is highly variable. Thus additional “triggers or stressors” either genetic and/or environmental are required for ARVC to manifest. Characteristically, the disease presents in athletic young adults and it is thought that exercise and increased myocardial demand and stress contributes to disease progression. It is known in a murine model of ARVC, due to plakoglobin haploinsufficiency, that exercise, specifically swimming, worsens the phenotype and that load reducing therapy can ameliorate it (Fabritz et al., 2011). Patients are advised to avoid strenuous exercise and are often prescribed β-blockers (Delmar and McKenna, 2010; Oxford et al., 2007). There have been other intriguing observations. Asimaki and colleagues noticed similarities between granulomatous myocarditis and ARVC namely mislocalisation of Pg away from cell-cell junctions in both conditions (Asimaki et al., 2011). Nuclear Pg is linked with suppression of Wnt/β-catenin signalling and upregulation of genes expressed in adipocytes (Garcia-Gras et al., 2006). Furthermore, in patients with ARVC there was an increase in a number of inflammatory cytokines and the application of these in neonatal rat myocytes led to Pg translocation (Asimaki et al., 2011). Thus inflammation and disease progression may be linked. |
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