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

• Published in: The American journal of pathology Vol. 187; no. 5; pp. 1134 - 1146
• Main Authors: Souza, Bruno Solano de Freitas, Silva, Daniela Nascimento, Carvalho, Rejane Hughes, Sampaio, Gabriela Louise de Almeida, Paredes, Bruno Diaz, Aragão França, Luciana, Azevedo, Carine Machado, Vasconcelos, Juliana Fraga, Meira, Cassio Santana, Neto, Paulo Chenaud, Macambira, Simone Garcia, da Silva, Kátia Nunes, Allahdadi, Kyan James, Tavora, Fabio, de Souza Neto, João David, dos Santos, Ricardo Ribeiro, Soares, Milena Botelho Pereira
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.05.2017
• Subjects: Acetylgalactosamine - pharmacology; Animals; Cell Proliferation - physiology; Cell Survival - physiology; Chagas Cardiomyopathy - metabolism; Chronic Disease; Collagen Type I - biosynthesis; Fibrosis - etiology; Fibrosis - metabolism; Galectin 3 - antagonists & inhibitors; Galectin 3 - metabolism; Heart Transplantation; Humans; Macrophages - metabolism; Mice; Mice, Inbred C57BL; Myocarditis - etiology; Myocarditis - metabolism; Myocardium - metabolism; Myocardium - pathology; Myofibroblasts - metabolism; Pathology; T-Lymphocytes - metabolism
• ISSN: 0002-9440; 1525-2191; 1525-2191
• DOI: 10.1016/j.ajpath.2017.01.016

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.