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International Journal of Cardiology May 2018
Topics: Arrhythmogenic Right Ventricular Dysplasia; Cardiomyopathies; Death, Sudden, Cardiac; Desmosomes; Humans; Myocarditis; Pregnancy
PubMed: 29544930
DOI: 10.1016/j.ijcard.2018.01.081 -
Frontiers in Physiology 2020Arrhythmogenic cardiomyopathy has been clinically defined since the 1980s and causes right or biventricular cardiomyopathy associated with ventricular arrhythmia.... (Review)
Review
Arrhythmogenic cardiomyopathy has been clinically defined since the 1980s and causes right or biventricular cardiomyopathy associated with ventricular arrhythmia. Although it is a rare cardiac disease, it is responsible for a significant proportion of sudden cardiac deaths, especially in athletes. The majority of patients with arrhythmogenic cardiomyopathy carry one or more genetic variants in desmosomal genes. In the 1990s, several knockout mouse models of genes encoding for desmosomal proteins involved in cell-cell adhesion revealed for the first time embryonic lethality due to cardiac defects. Influenced by these initial discoveries in mice, arrhythmogenic cardiomyopathy received an increasing interest in human cardiovascular genetics, leading to the discovery of mutations initially in desmosomal genes and later on in more than 25 different genes. Of note, even in the clinic, routine genetic diagnostics are important for risk prediction of patients and their relatives with arrhythmogenic cardiomyopathy. Based on improvements in genetic animal engineering, different transgenic, knock-in, or cardiac-specific knockout animal models for desmosomal and nondesmosomal proteins have been generated, leading to important discoveries in this field. Here, we present an overview about the existing animal models of arrhythmogenic cardiomyopathy with a focus on the underlying pathomechanism and its importance for understanding of this disease. Prospectively, novel mechanistic insights gained from the whole animal, organ, tissue, cellular, and molecular levels will lead to the development of efficient personalized therapies for treatment of arrhythmogenic cardiomyopathy.
PubMed: 32670084
DOI: 10.3389/fphys.2020.00624 -
Acta Physiologica (Oxford, England) Aug 2023Regulation of cadherin-mediated cell adhesion is crucial not only for maintaining tissue integrity and barrier function in the endothelium and epithelium but also for... (Review)
Review
Regulation of cadherin-mediated cell adhesion is crucial not only for maintaining tissue integrity and barrier function in the endothelium and epithelium but also for electromechanical coupling within the myocardium. Therefore, loss of cadherin-mediated adhesion causes various disorders, including vascular inflammation and desmosome-related diseases such as the autoimmune blistering skin dermatosis pemphigus and arrhythmogenic cardiomyopathy. Mechanisms regulating cadherin-mediated binding contribute to the pathogenesis of diseases and may also be used as therapeutic targets. Over the last 30 years, cyclic adenosine 3',5'-monophosphate (cAMP) has emerged as one of the master regulators of cell adhesion in endothelium and, more recently, also in epithelial cells as well as in cardiomyocytes. A broad spectrum of experimental models from vascular physiology and cell biology applied by different generations of researchers provided evidence that not only cadherins of endothelial adherens junctions (AJ) but also desmosomal contacts in keratinocytes and the cardiomyocyte intercalated discs are central targets in this scenario. The molecular mechanisms involve protein kinase A- and exchange protein directly activated by cAMP-mediated regulation of Rho family GTPases and S665 phosphorylation of the AJ and desmosome adaptor protein plakoglobin. In line with this, phosphodiesterase 4 inhibitors such as apremilast have been proposed as a therapeutic strategy to stabilize cadherin-mediated adhesion in pemphigus and may also be effective to treat other disorders where cadherin-mediated binding is compromised.
Topics: Humans; Pemphigus; Desmosomes; Cell Adhesion; Cadherins; Myocardium; Epithelium; Endothelium
PubMed: 37243909
DOI: 10.1111/apha.14006 -
Biochimica Et Biophysica Acta.... Aug 2017Arrhythmogenic cardiomyopathy (AC) is most commonly characterized as a disease of the intercalated disc that promotes abnormal cardiac conduction. Previously,... (Review)
Review
Arrhythmogenic cardiomyopathy (AC) is most commonly characterized as a disease of the intercalated disc that promotes abnormal cardiac conduction. Previously, arrhythmogenic cardiomyopathy was frequently referred to as arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D); however, genotype-phenotype studies have defined a broader phenotypic spectrum; with the identification of left-dominant and biventricular subtypes. Molecular insight into AC has primarily focused on mutations in desmosomal proteins and the downstream signaling pathways; however, desmosomal gene mutations can only be identified in approximately 50% of patients with AC. Animal and cellular studies have shown that in addition to abnormal biomechanical properties from changes in desmosome function, crosstalk from the desmosome to the nucleus, gap junctions, and ion channels are implicated in the pathobiology of AC. In this review, we highlight some of the newly identified genetic and epigenetic mechanisms that may lead to the development of AC including the role of the Hippo pathway and microRNAs. This article is part of a Special Issue entitled: Genetic and epigenetic control of heart failure - edited by Jun Ren & Megan Yingmei Zhang.
Topics: Animals; Arrhythmogenic Right Ventricular Dysplasia; Cell Nucleus; Desmosomes; Epigenesis, Genetic; Gap Junctions; Hippo Signaling Pathway; Humans; MicroRNAs; Protein Serine-Threonine Kinases; Signal Transduction
PubMed: 28454914
DOI: 10.1016/j.bbadis.2017.04.020 -
BioRxiv : the Preprint Server For... Sep 2023Desmosomes are transmembrane protein complexes that contribute to cell-cell adhesion in epithelia and other tissues. Here, we report the discovery of frequent genetic...
Desmosomes are transmembrane protein complexes that contribute to cell-cell adhesion in epithelia and other tissues. Here, we report the discovery of frequent genetic alterations in the desmosome in human cancers, with the strongest signal seen in cutaneous melanoma where desmosomes are mutated in over 70% of cases. In primary but not metastatic melanoma biopsies, the burden of coding mutations on desmosome genes associates with a strong reduction in desmosome gene expression. Analysis by spatial transcriptomics suggests that these expression decreases occur in keratinocytes in the microenvironment rather than in primary melanoma tumor cells. In further support of a microenvironmental origin, we find that loss-of-function knockdowns of the desmosome in keratinocytes yield markedly increased proliferation of adjacent melanocytes in keratinocyte/melanocyte co-cultures. Thus, gradual accumulation of desmosome mutations in neighboring cells may prime melanocytes for neoplastic transformation.
PubMed: 37786690
DOI: 10.1101/2023.09.19.558457 -
Open Biology Feb 2020Epithelial cells form highly organized polarized sheets with characteristic cell morphologies and tissue architecture. Cell-cell adhesion and intercellular communication... (Review)
Review
Epithelial cells form highly organized polarized sheets with characteristic cell morphologies and tissue architecture. Cell-cell adhesion and intercellular communication are prerequisites of such cohesive sheets of cells, and cell connectivity is mediated through several junctional assemblies, namely desmosomes, adherens, tight and gap junctions. These cell-cell junctions form signalling hubs that not only mediate cell-cell adhesion but impact on multiple aspects of cell behaviour, helping to coordinate epithelial cell shape, polarity and function. This review will focus on the tight and adherens junctions, constituents of the apical junctional complex, and aims to provide a comprehensive overview of the complex signalling that underlies junction assembly, integrity and plasticity.
Topics: Adherens Junctions; Animals; Cell Adhesion; Cell Communication; Cell Polarity; Desmosomes; Epithelial Cells; Gap Junctions; Gene Regulatory Networks; Humans; Intercellular Junctions
PubMed: 32070233
DOI: 10.1098/rsob.190278 -
Birth Defects Research Oct 2022Human stems cells have sparked many novel strategies for treating heart disease and for elucidating their underlying mechanisms. For example, arrhythmogenic right... (Review)
Review
Human stems cells have sparked many novel strategies for treating heart disease and for elucidating their underlying mechanisms. For example, arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited heart muscle disorder that is associated with fatal arrhythmias often occurring in healthy young adults. Fibro-fatty infiltrate, a clinical hallmark, progresses with the disease and can develop across both ventricles. Pathogenic variants in genes have been identified, with most being responsible for encoding cardiac desmosome proteins that reside at myocyte boundaries that are critical for cell-to-cell coupling. Despite some understanding of the molecular signaling mechanisms associated with ARVC mutations, their relationship with arrhythmogenesis is complex and not well understood for a monogenetic disorder. This review article focuses on arrhythmia mechanisms in ARVC based on clinical and animal studies and their relationship with disease causing variants. We also discuss the ways in which stem cells can be leveraged to improve our understanding of the role cardiac myocytes, nonmyocytes, metabolic signals, and inflammatory mediators play in an early onset disease such as ARVC.
Topics: Arrhythmogenic Right Ventricular Dysplasia; Heart Ventricles; Humans; Mutation; Stem Cells
PubMed: 35396927
DOI: 10.1002/bdr2.2010 -
Biochimica Et Biophysica Acta.... Sep 2020Desmosomes are cadherin-based adhesion structures that mechanically couple the intermediate filament cytoskeleton of adjacent cells to confer mechanical stress... (Review)
Review
Desmosomes are cadherin-based adhesion structures that mechanically couple the intermediate filament cytoskeleton of adjacent cells to confer mechanical stress resistance to tissues. We have recently described desmosomes as mesoscale lipid raft membrane domains that depend on raft dynamics for assembly, function, and disassembly. Lipid raft microdomains are regions of the plasma membrane enriched in sphingolipids and cholesterol. These domains participate in membrane domain heterogeneity, signaling and membrane trafficking. Cellular structures known to be dependent on raft dynamics include the post-synaptic density in neurons, the immunological synapse, and intercellular junctions, including desmosomes. In this review, we discuss the current state of the desmosome field and put forward new hypotheses for the role of lipid rafts in desmosome adhesion, signaling and epidermal homeostasis. Furthermore, we propose that differential lipid raft affinity of intercellular junction proteins is a central driving force in the organization of the epithelial apical junctional complex.
Topics: Cadherins; Cell Adhesion; Cholesterol; Cytoskeleton; Desmosomes; Epidermis; Humans; Membrane Lipids; Membrane Microdomains; Signal Transduction; Sphingolipids
PubMed: 32376221
DOI: 10.1016/j.bbamem.2020.183329 -
Heart Failure Clinics Jan 2022Naxos disease is a recessively inherited pattern of arrhythmogenic cardiomyopathy with palmoplantar keratoderma and woolly hair. The causative mutation identified in... (Review)
Review
Naxos disease is a recessively inherited pattern of arrhythmogenic cardiomyopathy with palmoplantar keratoderma and woolly hair. The causative mutation identified in plakoglobin protein gene indicated a potential role of the desmosomal protein complex as culprit for cardiomyopathy. In the context of a family, the early evident cutaneous features may serve as a clinical screening tool to spot arrhythmogenic cardiomyopathy in subclinical stage. "Myocarditis-like episodes" may step up the disease evolution or mark a transition from concealed to symptomatic cardiomyopathy phase. Arrhythmogenic cardiomyopathy in Naxos disease shows increased penetrance and phenotypic expression but its arrhythmic risk is analogous to dominant forms.
Topics: Arrhythmogenic Right Ventricular Dysplasia; Cardiomyopathies; Hair Diseases; Humans; Keratoderma, Palmoplantar
PubMed: 34776086
DOI: 10.1016/j.hfc.2021.07.010 -
Essays in Biochemistry Oct 2019Migration of epithelial cells is fundamental to multiple developmental processes, epithelial tissue morphogenesis and maintenance, wound healing and metastasis. While... (Review)
Review
Migration of epithelial cells is fundamental to multiple developmental processes, epithelial tissue morphogenesis and maintenance, wound healing and metastasis. While migrating epithelial cells utilize the basic acto-myosin based machinery as do other non-epithelial cells, they are distinguished by their copious keratin intermediate filament (KF) cytoskeleton, which comprises differentially expressed members of two large multigene families and presents highly complex patterns of post-translational modification. We will discuss how the unique mechanophysical and biochemical properties conferred by the different keratin isotypes and their modifications serve as finely tunable modulators of epithelial cell migration. We will furthermore argue that KFs together with their associated desmosomal cell-cell junctions and hemidesmosomal cell-extracellular matrix (ECM) adhesions serve as important counterbalances to the contractile acto-myosin apparatus either allowing and optimizing directed cell migration or preventing it. The differential keratin expression in leaders and followers of collectively migrating epithelial cell sheets provides a compelling example of isotype-specific keratin functions. Taken together, we conclude that the expression levels and specific combination of keratins impinge on cell migration by conferring biomechanical properties on any given epithelial cell affecting cytoplasmic viscoelasticity and adhesion to neighboring cells and the ECM.
Topics: Actin Cytoskeleton; Actins; Animals; Cell Movement; Desmosomes; Epithelial Cells; Hemidesmosomes; Humans; Intermediate Filaments; Keratins; Wound Healing
PubMed: 31652439
DOI: 10.1042/EBC20190017