MIRAGE · MicroRNAs as therapeutic targets for ARVC.

MicroRNAs as therapeutic targets for ARVC.

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a genetic cardiac disease mainly characterised by the progressive substitution of the myocardium with fatty or fibro-fatty tissue. Although initially thought to be rare, ARVC is the second most common cause of unexpected sudden death in the young and may account for as many as 22,4% of sudden death among athletes. Clinically, ARVC is characterised by ventricular arrhythmias, often associated with syncope and sudden cardiac death, which can be its first manifestation, and shows wide heterogeneity, with inter- and intra-familial variability, ranging from benign to malignant forms. This wide clinical spectrum complicates the diagnosis of the disease, making the identification of at risk subjects difficult. Moreover, as a cause of sudden death, ARVC has devastating psychosocial and economic consequences as many victims are relatively young adults in their productive years of life. Despite the fact that the disease has been described almost thirty years ago, the pathogenic mechanisms leading to its development have not been elucidated yet. The understanding of the molecular dynamics related to this deadly disease and the improvement of its diagnosis, hence, is crucial. Together with modifier genes, common sequence variants, and environmental as well as endogenous factors (e.g., age, gender), epigenetic mechanisms are hypothesised to account for a large part of the variation between individuals. It is clear that epigenetic modifiers, such as RNA-based mechanisms, are molecular targets for disadvantageous environmental stimuli and may lead to the onset of complex and heterogeneous diseases such as ARVC. MicroRNAs (miRNAs) are a class of short, approximately 22 nucleotides, non-coding RNAs that switch off their target gene under different stimuli. Compelling evidence shows that distinct forms of heart failure are characterised by specific miRNA mechanisms, opening new treatment paradigms aimed at pivotal miRNAs for each heart failure stratum. It has been estimated that the human heart expresses more than 800 miRNAs. For ARVC, no study has reported cardiac tissue miRNA involvement that may provide insights into the specifics of the disease. The overall objective of this study is to provide new insights to study the disease mechanisms underlying the development of ARVC and to identify novel RNA-based targets in mouse models and ARVC patients. To reach this aim, we analysed both the RNA from the heart of a transgenic mouse model for ARVC overexpressing a mutation in DSG2 gene found in a human patient as well as the RNA from ARVC patients’ plasma. In order to take into account biological gender differences, an equal number of samples (both from transgenic male and female mice and humans) was chosen. We were able to determine the cardiac and circulating miRNA profiling associated with ARVC, thus opening the venue to further investigation on ARVC. The results obtained in this study provide new insights in understanding the pathogenesis of the disease and in the development of novel tailored RNA-based drugs that take into account the diversity of the patients affected with different cardiac diseases. Moreover, our data on circulating miRNAs will be used to define novel non-invasive biomarkers that will improve the complicated diagnosis of the disease.

Data: CORDIS, © European Union