Vias de sinalização alteradas no coração de camundongos com redução na expressão da proteína induzida por estresse (STI1) tratados com isoproterenol

• Autor(a) principal: Victor Moura Vidal Costa
• Data de Publicação: 2021
• Tipo de documento: Dissertação
• Idioma: por
• Título da fonte: Repositório Institucional da UFMG
• Texto Completo: http://hdl.handle.net/1843/54094
• topic: Coração; STI1; Isoproterenol; Hipertrofia cardíaca; Fisiologia; Coração Isoproterenol; Cardiomegalia; Proteínas de choque térmico

Chaperone molecules have been described to play an important role during the development of heart disease. Stress-inducible protein 1 (STI1) is an important cochaperone of the Hsp70 / Hsp90 machinery, widely studied in neurons, where it plays a role in protein maturation and cytoprotection against cellular stress events. Despite STI1 having its expression in the heart described since 2009, its role in this organ is still unknown. In this context, our group was a pioneer in showing the presence of STI1 in the hearts of human patients and its reduction in hearts with heart failure. We also show the cardioprotective role of STI1 in a model of adrenergic hyperactivation induced by isoproterenol (ISO). Although we have already established the relevance of STI1 to the adrenergic stress response in the heart, the mechanisms involved in this process are still unknown. Thus, the aim of this work was to evaluate the altered signaling pathways in mouse hearts with reduced expression of STI1 (STI1+/- ) in response to ISO treatment. For this, we performed a "Bottom up" proteomic assay in order to evaluate and predict the alterations of pathways in these contexts. We identified that the STI1+/- /ISO mice showed alterations in several cellular pathways, with emphasis on the inhibition of the nuclear factor 2 pathway related to erythroid 2 (NRF2), which was later validated by means of immunofluorescence in the cardiac tissue of STI1+/- /ISO mice when compared to WT/ISO. We also identified the prediction of cardiac necrosis and fibrosis events in STI1+/- /ISO mice, the latter being validated by histology using the picrosirius technique and qRT-PCR for collagen 3. Interestingly, we found several proteins related to protein synthesis and degradation down-regulated in the STI1+/-/ISO group, indicating that the reduction in STI1 levels compromises protein synthesis in the heart under stress conditions. This result, in a way, is in line with the absence of cardiomyocyte hypertrophy in the STI1+/- /ISO group when compared to the WT/ISO group, since hypertrophic growth demands the protein synthesis machinery. In conclusion, these data point to STI1- dependent cellular mediators in the heart, which mainly include pathways related to protein synthesis, which, in turn, prevents the onset of cardiomyocyte hypertrophy. Thus, our work opens important perspectives for more robust studies about the role of STI1 in cardiac stress, which may generate new therapeutic strategies for heart disease.