Abstract
Cardiac fibrosis is characterized by an excessive accumulation of extracellular matrix components, including collagens. Galectin-3 (Gal-3) and Cardiotrophin-1 (CT-1) are two profibrotic molecules that mediate Aldosterone (Aldo)-induced cardiac fibrosis. However the underlying mechanisms are not well defined. Our aim is to characterize changes in the proteome of human cardiac fibroblasts treated with Aldo, Gal-3 or CT-1 to identify new common proteins that might be new therapeutic targets in cardiac fibrosis. Using a quantitative proteomic approach in human cardiac fibroblasts, our results show that Aldo, Gal-3 and CT-1 modified the expression of 30, 17 and 89 proteins respectively, being common the reticulocalbin (RCN) family members. RCN-3 down-regulation triggered by Aldo, Gal-3 and CT-1 was verified. Treatment with recombinant RCN-3 decreased collagens expression in human cardiac fibroblasts through Akt phosphorylation. Interestingly, CRISPR/Cas9-mediated activation of RCN-3 decreased collagen production in human cardiac fibroblasts. In addition, recombinant RCN-3 blocked the profibrotic effects of Aldo, Gal-3 and CT-1. Interestingly, RCN-3 blunted the increase in collagens expression induced by other profibrotic stimuli, angiotensin II, in human cardiac fibroblasts. Our results suggest that RCN-3 emerges as a new potential negative regulator of collagen production and could represent a therapeutic target in the context of cardiac fibrosis.
Highlights
Cardiotrophin-1 (CT-1) as two molecules up-regulated by Aldo/MR5–7
Gal-3 and CT-1 emerge as key factors in the cardiac remodeling induced by Aldo associated with cardiac hypertrophy and fibrosis, facilitating cardiac dysfunction[6,13]
In order to identify the common molecules or pathways activated by Aldo, Gal-3 and CT-1 in cardiac fibroblasts leading to collagen production, a proteomic approach was performed
Summary
Cardiotrophin-1 (CT-1) as two molecules up-regulated by Aldo/MR5–7. Gal-3 directly increases the synthesis of ECM components and mediates the profibrotic actions of Aldo in cardiac fibroblasts[6]. Gal-3 and CT-1 emerge as key factors in the cardiac remodeling induced by Aldo associated with cardiac hypertrophy and fibrosis, facilitating cardiac dysfunction[6,13]. Despite the cardiac profibrotic actions of Aldo, Gal-3 and CT-1, the underlying mechanisms are not well defined. In order to identify the common molecules or pathways activated by Aldo, Gal-3 and CT-1 in cardiac fibroblasts leading to collagen production, a proteomic approach was performed. We identified Reticulocalbin 3 (RCN-3) as a common molecule down-regulated by Aldo, Gal-3 and CT-1. RCN-3 emerges as a new potential negative regulator of collagen production and could represent a promising therapeutic target in the context of cardiac fibrosis
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