Unravelling Role of miRNA-mRNA Interactome in Pathophysiology of Arrhythmogenic Cardiomyopathy [mRNA-seq]
Arrhythmogenic cardiomyopathy is an inherited entity characterized by irregular cell-cell adhesion, cardiomyocyte death, fibro-fatty replacement of ventricular myocytes, leading to malignant ventricular arrythmias, contractile dysfunction and sudden cardiac death. Pathogenic variants in genes that encode desmosome are the predominant cause of arrhythmogenic cardiomyopathy. Moreover, signalling pathways such as Wnt/ß-catenin and transforming growth factor-ß have been involved in the disease progression. However, still little is known about the molecular pathophysiological mechanisms that underlie arrhythmogenic cardiomyopathy pathogenesis. We used mRNA and small RNA sequencing to analyse the transcriptome of health and arrhythmogenic cardiomyopathy autopsied human hearts. Our results showed 697 differentially expressed genes, and eight differentially expressed miRNAs. Functional enrichment revealed mitochondrial respiratory-related pathways, impaired response to oxidative stress, apoptotic signalling pathway, inflammatory response-related and extracellular matrix response pathways. Furthermore, analysis of miRNA-mRNA interactome identified eleven negatively correlated miRNA-target pairs for arrhythmogenic cardiomyopathy. Our finding revealed novel arrhythmogenic cardiomyopathy-related miRNAs with important regulatory function in disease pathogenesis highlighting their value as potential key targets for therapeutic approaches. Overall design: To investigate the molecular pathophysiological mechanisms underlying arrhythmogenic cardiomyopathy. By employing mRNA and small RNA sequencing, we aimed to analyze the transcriptome of healthy and arrhythmogenic cardiomyopathy-affected human hearts, identifying differentially expressed genes and miRNAs. Additionally, we sought to elucidate the functional pathways and miRNA-mRNA interactions involved in the disease, with the goal of discovering novel miRNAs with regulatory functions that could serve as potential therapeutic targets for arrhythmogenic cardiomyopathy.