Pharmacological modulation of the Wnt/β-catenin signaling rescues pathological signatures of Arrhythmogenic Cardiomyopathy in desmoplakin-deficient zebrafish models.

Arrhythmogenic Cardiomyopathy (AC) is an inherited heart disorder characterized by the progressive fibro-fatty substitution of the ventricular myocardium, which jeopardizes the transmission of the contraction signal and increases the risk of a sudden cardiac death, particularly in young adults and athletes. About 50% of AC cases are determined by mutations in genes encoding for desmosomal proteins, including desmoplakin (DSP), whose mutation characterizes our zebrafish models. In this thesis we aimed to characterize stable dsp knock-out (KO) zebrafish lines to identify early pathological features, at rest and under physical effort, and test the efficacy of pathway-directed drugs. At larval stage, mutant larvae presented cardiac-specific abnormalities associated with developmental delay, bradycardia and alteration of the Wnt/β-catenin pathway – a key modulator of AC pathogenesis. A series of pharmacological treatments with SB216763, an agonist of the Wnt/β-catenin pathway, rescued pathway activity, bradycardia phenotype and cardiac-specific alterations. At adult stage, histological analysis of mutant zebrafish hearts revealed an abnormal ventricular shape, with vessels dilation and adipocytes infiltration, and a general worsening of the pathological phenotype after physical training. To conclude, our work depicts zebrafish as a suitable system to recapitulate, study and treat AC through the modulation of Wnt/β-catenin signaling.