Association of Cardiac Galectin-3 Expression, Myocarditis, and Fibrosis in Chronic Chagas Disease Cardiomyopathy

Abstract

Chronic Chagas disease cardiomyopathy, caused by Trypanosoma cruzi infection, is a major cause of heart failure in Latin America. Galectin-3 (Gal-3) has been linked to cardiac remodeling and poor prognosis in heart failure of different etiologies. Herein, we investigated the involvement of Gal-3 in the disease pathogenesis and its role as a target for disease intervention. Gal-3 expression in mouse hearts was evaluated during T. cruzi infection by confocal microscopy and flow cytometry analysis, showing a high expression in macrophages, T cells, and fibroblasts. In vitro studies using Gal-3 knockdown in cardiac fibroblasts demonstrated that Gal-3 regulates cell survival, proliferation, and type I collagen synthesis. In vivo blockade of Gal-3 with N-acetyl-d-lactosamine in T. cruzi-infected mice led to a significant reduction of cardiac fibrosis and inflammation in the heart. Moreover, a modulation in the expression of proinflammatory genes in the heart was observed. Finally, histological analysis in human heart samples obtained from subjects with Chagas disease who underwent heart transplantation showed the expression of Gal-3 in areas of inflammation, similar to the mouse model. Our results indicate that Gal-3 plays a role in the pathogenesis of experimental chronic Chagas disease, favoring inflammation and fibrogenesis. Moreover, by demonstrating Gal-3 expression in human hearts, our finding reinforces that this protein could be a novel target for drug development for Chagas cardiomyopathy.

Galectin-3 Knockdown Impairs Survival, Migration, and Immunomodulatory Actions of Mesenchymal Stromal Cells in a Mouse Model of Chagas Disease Cardiomyopathy

“…Stable Gal-3 knockdown was achieved by MSC or J774 macrophages by transduction with lentiviral vectors carrying a shRNA sequence targeting Lgals3 gene or scrambled control (Lgals3_shRNA1 5′-GATTTCAGGAGAGGGAATGAT-3′; one Lgals3_scrbl_shRNA 5′-AGGTATGAGTCGAGATTGAGA-3′), as previously described [18]. Culture medium was replaced and the cells were cultured for an additional 48 h, being assessed for GFP reporter gene expression by using an inverted fluorescence microscope (Eclipse Ti-E; Nikon, Tokyo, Japan).…”

“…Previously, it was demonstrated that transplantation of MSC into mice chronically infected with T. cruzi caused a reduction of myocarditis and modulation of fibrosis [14–16]. Additionally, we have shown that Gal-3 expression is increased in the hearts of chronic chagasic mice and in human samples [17, 18]. T. cruzi infection induces increased Gal-3 expression in different cell types, which favors parasite adhesion, migration, invasion, and reduces antiparasitic immune responses [19–23].…”

Myocardial fibrosis in chagas disease and molecules related to fibrosis

“…One of those articles performed histological analysis in human heart samples obtained from subjects with Chagas disease who underwent heart transplantation. They observed the presence of galectin‐3‐expressing cells, within the inflammatory foci and surrounding the myofibres, which may indicate that this protein could be a novel target for drug development for Chagas cardiomyopathy . On the other hand, other studies with Chagas patients did not relate any relation between galectin‐e and fibrosis.…”

“…Galectin‐3 is a molecule which has been associated with an increased risk of heart failure and mortality in other cardiopathies that are not Chagas disease . Animal models of infection with Trypanosoma cruzi pointed to a correlation between galectin‐3 and fibrosis . One of those articles performed histological analysis in human heart samples obtained from subjects with Chagas disease who underwent heart transplantation.…”

Biomarkers in Heart Failure

“…The main biological function of galectin-3 is to activate the fibroblasts for further collagen synthesis [6]. Recent pre-clinical and clinical studies revealed the pivotal role of galectin-3 in progressive accumulation of extracellular matrix leading to cardiac fibrosis, cardiac remodeling, and worsening cardiac performances associated with impaired systolic and diastolic function, dilation of cardiac cavities, and induce of cardiac arrhythmias [7]. Increased expression of galectin-3 was found in acute HF, ADHF, and chronic HFrEF/HFpEF regardless etiology of disease [8].…”