Identificazione di target terapeutici per lo scompenso cardiaco attraverso studi in vitro e in vivo

ABSTRACT Identification of therapeutic targets for heart failure through in vitro and in vivo studies. Heart failure is a multi-organ disease, characterized by the heart’s inability to supply tissues with the necessary amount of blood and oxygen to meet metabolic demands. Myocardial fibrosis is one of the hallmarks of all forms of heart failure. All forms of myocardial fibrosis, are characterized by a complex process that results in an accumulation of extracellular matrix (ECM). In the fibrotic process, myofibroblasts responsible for regulating collagen turnover play an important role and they are able to contract. TGF-β is a pro-fibrotic cytokine responsible for converting fibroblasts into myofibroblasts, increases the synthesis of cell matrix proteins, reduces the production of metal proteases and inhibits by the synthesis of TIMPs (Metalloprotease Inhibitor) the degradation of the ECM. In addition to TGF-β, one of the pathways involved in the fibrotic process is the Wnt-β pathway. Wnt after bound to its specific receptor, creates a complex that establishes b-catenin that translocation at the nuclear level is able to modulate the expression of genes involved in the fibrotic process. A key role in fibrosis is played by adenosine. Adenosine is a widely distributed nucleotide, and is an important regulator of heart function. Adenosine receptors can be involved in both pro-fibrotic and anti-fibrotic mechanisms. Currently, knowledge of the pathological and molecular mechanisms that lead to the onset of heart failure, is one of the challenges of today’s scientific world to prevent and treat this disease. The aim of the thesis is to identify new targets for the therapeutic treatment of heart failure through in vitro and in vivo models