MOLECULAR PROCESSES UNDERLYING HYPERTROPHY IN ICEFISH AS PROMISING TOOLS TO TRANSLATE IN HUMANS MODELS

Pathological hypertrophic remodelling is typically irreversible and shows a reduced number of fibres and slow repolarization of the left ventricle. Potential therapeutic targets for treating hypertrophy and heart failure are focused on the knowledge of the signal molecules involved [1] or the metabolism pathways in the process [2]. Humans and fish share the mechanisms of some pathological pathways that lead to cardiac hypertrophy and miRNAs are particularly key regulators of cardiac size [3,4]. Antarctic icefish (Chionodraco hamatus, Channichthyidae-Notothenioids) are invaluable for answering some main biological questions. They are able to survive to −1.8 °C in seawater and are the only cold-blood vertebrates that lack haemoglobin; possess a vascularisation enhancement and a hypertrophic heart [5]. The heart can displace large systolic volumes at a low rate and relatively low pressure, with large ventricular fillings (high ventricular compliance). The analysis of RNA extracted from the ventricular portion of the icefish heart has revealed a downregulation of miRNAs (i.e.1,133a,b) similar to the fish and mammalian models. These miRNAs seem to control cardiac hypertrophy [6,7]. Contemporary, the immunohistochemical analysis reveals the expression of embryonic genes such as GATA4, WT1, NFAT2 [8] and,also RACK1 which we have identified as a key molecule in hypertrophy-activated genes in fish. These preliminary results indicate a promising pipeline among fish and human-3D-organoid culture models. Identifying novel therapeutic targets using innovative approaches is critical to developing new therapies. This Project is funded by PNRA0000022.