Desmosomes: emerging pathways and non-canonical functions in cardiac arrhythmias and disease

Abstract

Desmosomes are critical adhesion structures in cardiomyocytes, with mutation/loss linked to the heritable cardiac disease, arrhythmogenic right ventricular cardiomyopathy (ARVC). Early studies revealed the ability of desmosomal protein loss to trigger ARVC disease features including structural remodeling, arrhythmias, and inflammation; however, the precise mechanisms contributing to diverse disease presentations are not fully understood. Recent mechanistic studies demonstrated the protein degradation component CSN6 is a resident cardiac desmosomal protein which selectively restricts cardiomyocyte desmosomal degradation and disease. This suggests defects in protein degradation can trigger the structural remodeling underlying ARVC. Additionally, a subset of ARVC-related mutations show enhanced vulnerability to calpain-mediated degradation, further supporting the relevance of these mechanisms in disease. Desmosomal gene mutations/loss has been shown to impact arrhythmogenic pathways in the absence of structural disease within ARVC patients and model systems. Studies have shown the involvement of connexins, calcium handling machinery, and sodium channels as early drivers of arrhythmias, suggesting these may be distinct pathways regulating electrical function from the desmosome. Emerging evidence has suggested inflammation may be an early mechanism in disease pathogenesis, as clinical reports have shown an overlap between myocarditis and ARVC. Recent studies focus on the association between desmosomal mutations/loss and inflammatory processes including autoantibodies and signaling pathways as a way to understand the involvement of inflammation in ARVC pathogenesis. A specific focus will be to dissect ongoing fields of investigation to highlight diverse pathogenic pathways associated with desmosomal mutations/loss.

Autophagy and Endoplasmic Reticulum Stress during Onset and Progression of Arrhythmogenic Cardiomyopathy

“…Strikingly, we observed that ER/SR stress markers normalize in young adult mice with fully matured hearts and fully developed scar tissue (10–12 weeks) but increase again in older animals, especially in the right ventricular wall. We take this as evidence for deteriorating ER/SR function during chronic disease progression, which goes along with reduced ryanodine receptor 2 expression and was also described in conjunction with plakophilin 2 mutation [ 85 , 86 ]. In addition, reduced Serca2a expression was observed in right ventricles of Dsg2 MT mice during chronic AC progression [ 26 ], in the failing right ventricles of AC patients [ 26 ] and other cardiomyopathies [ 87 ].…”

“…In the case of murine cardiomyocytes, an increased frequency of spontaneous Ca 2+ release events was observed [ 89 , 90 ]. Some of these changes might be responsible for the susceptibility to arrhythmias characterizing the clinical phenotype of AC [ 86 , 95 , 96 , 97 ].…”

Arrhythmogenic cardiomyopathy as a myogenic disease: highlights from cardiomyocytes derived from human induced pluripotent stem cells

“…Electrical remodeling, due to the destabilization of desmosomes, is a hallmark of ACM ( Rizzo et al, 2012 ; Stevens et al, 2022 ). Desmosomes are physically close to gap junctions, belonging to the same macromolecular complex ( Sato et al, 2011 ; Zhang J et al, 2021 ). Connexins are transmembrane proteins forming gap junctions enabling intercellular communication ( Desplantez et al, 2007 ; Dhein and Salameh, 2021 ).…”

Cardiac AAV9:PKP2 Gene Therapy Reduces Ventricular Arrhythmias, Reverses Adverse Remodeling, and Reduces Mortality in a Mouse Model of ARVC

“…Reduction of Connexin 43 (Cx43), a critical component of GJs, results in compromised electrical coupling and heterogeneous conduction between cardiomyocytes (Oxford et al, 2007;Rodriguez-Sinovas et al, 2021). These structural corruptions trigger cell death response, inflammatory infiltration, and metabolic perturbation that underpin clinical manifestations of electrical instability, cardiac structural deterioration, fibrofatty infiltration, and heart failure (Asatryan et al 2021;Austin et al, 2019;Cerrone et al, 2017;Chen et al, 2014;Dubash et al, 2016;Pérez-Hernández et al, 2022;Reichart et al, 2022;Song et al, 2020;Zhang et al, 2021).…”