| dc.description.abstract | 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. | |
