Arrhythmogenic cardiomyopathy: An in-depth look at molecular mechanisms and clinical correlates

Desmosomes as Signaling Hubs in the Regulation of Cell Behavior

“…Beyond structural functions preserving mechanical resistance of tissues, desmosomal components are also indispensable for intracellular signaling. As extensively described in various recent reviews ( Najor, 2018 ; Costa et al, 2020 ; Egami et al, 2020 ; Chen et al, 2021 ; Lee and McGrath, 2021 ; Mohammed and Chidgey, 2021 ) numerous diseases of the skin and/or the heart arise if desmosomal proteins are compromised. These disorders show a plethora of clinical manifestations and are often accompanied by dysregulated proliferation and/or inflammation.…”

“…To illustrate the close connection between structural and signaling functions of desmosomes, we focus here on desmosome in epidermal keratinocytes and their regulation by signaling pathways that affect proliferation, survival, differentiation, and inflammation as well as the impact of desmosomal proteins on these pathways. For detailed information on assembly of desmosomes and their interplay with tight junctions, adherens junctions and gap junctions as well as on their role in the heart we refer to recent reviews ( Patel and Green, 2014 ; Hatzfeld et al, 2017 ; Piven and Winata, 2017 ; Garcia et al, 2018 ; Green et al, 2019 ; Costa et al, 2020 ; Gerull and Brodehl, 2020 ).…”

Arrhythmogenic cardiomyopathy: An in-depth look at molecular mechanisms and clinical correlates

“…14 RNA sequencing-based transcriptome profiling of cardiac tissue suggests actin disorganization and disruption of focal adhesion pathways but not Wnt signalling as pathogenic mechanisms of FLNC-driven ACM, distinct from the postulated molecular pathways of classic ARVC. 5,15 On a different note, inclusion of biventricular forms in the ACM spectrum, has increased the degree of overlap between ACM and inflammatory diseases. It is not rare for ACM patients to first present with ECG changes and cardiac biomarkers consistent with myocarditis.…”

“…4 In this issue of Trends in Cardiovascular Medicine, Costa et al provide a highly comprehensive review of the currently known molecular mechanisms underlying ACM. 5 In-depth understanding of these mechanisms is of pivotal importance not only for improving diagnosis but also for the development of much-needed mechanism-based therapies.…”

Roles for Ndel1 in keratin organization and desmosome function

“…Disruption of desmosomes results in a range of disorders of the skin from mild cases presenting with skin thickening to lethal blistering (Kottke et al, 2006). Mutations in genes for desmosomal proteins also cause arrhythmogenic cardiomyopathya heart defect characterized by fibro-fatty infiltrates (Delmar and McKenna, 2010) (Costa et al, 2020). The major connection between desmosomes and IFs is provided by desmoplakina core component of the desmosomal plaque that directly binds to the epithelial keratin filaments and the desmin filaments in cardiac muscle (Bornslaeger et al, 1996;Gallicano et al, 1998;Kouklis et al, 1994;Stappenbeck et al, 1993).…”