A NOVEL EXPERIMENTAL MODEL FOR INVESTIGATING ON MOLECULAR PATHOGENESIS OF ARRHYTHMOGENIC RIGHT VENTRICULAR CARDIOMYOPATHY

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a dominant, degenerative cardiomyopathy, frequently involved in sudden death of asymptomatic athletes and teenagers. In spite of the recent discovery of genes whose mutations cause ARVCs, early molecular events leading to cardiomyocyte degeneration, to fibrosis and to adipose substitution remain elusive. According to our hypothesis, myocardial tissue of the ventricular free wall would be stretched by increased load of the ventricle, occurring under physical effort. In this situation, intracellular calcium concentration in cardiomyocytes would increase, due to stretch-activated calcium channels. Volume overload in a ventricle carrying genetically defective intercellular junctions (as in case of mutant Plakoglobin, Desmoplakin or plakophilin) would produce over-stretch and, hence, excessive calcium load. Equally, stretched myocardiocytes with normal intercellular junctions, but with defective (leaky) Ryanodine receptors, would be subjected to increase of intracellular calcium concentration, leading to chronic calcium overload. Present project aims at setting up a novel experimental model for investigating on molecular pathogenesis of ARVCs. By classical fluorescent indicators, we aim at detecting differences in intracellular calcium transients in response to strain in normal compared with defective cardiomyocytes (expression of selected desmosomal genes inhibited by small RNA molecules or oligonucleotides). An additional aim is to detect differences in the rate of induced apoptosis, in the same experimental setup. In perspective, such model should prove useful for studying different inherited cardiomyopathies as well as for assessing effects of selected pharmacological treatments on defective cardiomyocytes.