Non Coding RNAs as Regulators of Wnt/β-Catenin and Hippo Pathways in Arrhythmogenic Cardiomyopathy

Abstract

Arrhythmogenic cardiomyopathy (ACM) is an inherited cardiomyopathy histologically characterized by the replacement of myocardium by fibrofatty infiltration, cardiomyocyte loss, and inflammation. ACM has been defined as a desmosomal disease because most of the mutations causing the disease are located in genes encoding desmosomal proteins. Interestingly, the instable structures of these intercellular junctions in this disease are closely related to a perturbed Wnt/β-catenin pathway. Imbalance in the Wnt/β-catenin signaling and also in the crosslinked Hippo pathway leads to the transcription of proadipogenic and profibrotic genes. Aiming to shed light on the mechanisms by which Wnt/β-catenin and Hippo pathways modulate the progression of the pathological ACM phenotype, the study of non-coding RNAs (ncRNAs) has emerged as a potential source of actionable targets. ncRNAs comprise a wide range of RNA species (short, large, linear, circular) which are able to finely tune gene expression and determine the final phenotype. Some share recognition sites, thus referred to as competing endogenous RNAs (ceRNAs), and ensure a coordinating action. Recent cancer research studies regarding the key role of ceRNAs in Wnt/β-catenin and Hippo pathways modulation pave the way to better understanding the molecular mechanisms underlying ACM.

Non-coding RNAs as regulators of the Hippo pathway in cardiac development and cardiovascular disease

“…Piquer-Gil et al ( Piquer-Gil et al, 2022 ) also reported that axes such as lncRNA UCA1/miR-18a/YAP and lncRNA FLVCR1-AS1/miR-513/YAP promote YAP activity through miRNA inhibition. In addition, there may be a bidirectional relationship between YAP/TAZ and ncRNA.…”

“…For example, YAP and lncRNA RP11-323N12.5 can bidirectionally regulate the activities of both genes, thereby promoting the expression of genes regulated by YAP. However, the role of these targets in heart disease need to be further investigated ( Piquer-Gil et al, 2022 ).…”

miRNAs: From Master Regulators of Gene Expression to Biomarkers Involved in Intercellular Communication

“…For instance, Leavy et al [24] reported that the impairment of normal brain maturation caused by early life brain injury (such as hypoxia) is accompanied by modification of miRNA expression, possibly driven by cMYC. In their review, Piquer-Gil et al [25] focused on the importance of the balance between two key pathways (Wnt/β-catenin and Hippo pathways) in the progression of the pathological arrhythmogenic cardiomyopathy (ACM) phenotype, a form of heart disease that can cause sudden death. The authors, by using data from cancer research, hypothesized that non-coding RNA (including miRNAs) could play a role in regulating these pathways in ACM.…”

Non-Coding RNAs and Gut Microbiota in the Pathogenesis of Cardiac Arrhythmias: The Latest Update

“…For example, the miR-145-5p and miR-585-3p are associated with the standing position of Brugada patients, which might be the potential utility of leucocyte-derived miRNAs as prognostic biomarkers for Brugada syndrome [ 31 , 32 ]. Arrhythmogenic cardiomyopathy is a genetically determined disorder caused by mutations in proteins constituting desmosomes, which might be an inherited cardiomyopathy histologically categorized by the replacement of myocardium with inflammation, fibrofatty infiltration, and cardiomyocyte loss [ 33 ]. Inflammation might also be involved in the pathogenesis of arrhythmogenic cardiomyopathy with various inflammatory cytokines [ 34 ].…”