Therapeutic miR-21 Silencing Reduces Cardiac Fibrosis and Modulates Inflammatory Response in Chronic Chagas Disease

• Published in: International journal of molecular sciences Vol. 22; no. 7; p. 3307
• Main Authors: Nonaka, Carolina Kymie Vasques, Sampaio, Gabriela Louise, de Aragão França, Luciana, Cavalcante, Bruno Raphael, Silva, Katia Nunes, Khouri, Ricardo, Torres, Felipe Guimarães, Meira, Cassio Santana, de Souza Santos, Emanuelle, Macedo, Carolina Thé, Paredes, Bruno Diaz, Rocha, Vinicius Pinto Costa, Rogatto, Silvia Regina, Ribeiro dos Santos, Ricardo, Souza, Bruno Solano de Freitas, Soares, Milena Botelho Pereira
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 24.03.2021; MDPI
• Subjects: Animals; Cardiomyopathy; Cell cycle; Cell growth; Cells, Cultured; Chagas Cardiomyopathy - genetics; Chagas Cardiomyopathy - metabolism; Chagas Cardiomyopathy - pathology; Chagas Cardiomyopathy - therapy; Chagas disease; Collagen; Collagen - genetics; Collagen - metabolism; Datasets; Extracellular matrix; Fibroblasts; Fibrosis; Gene expression; Humans; Infections; Male; Mice; Mice, Inbred C57BL; MicroRNAs - genetics; MicroRNAs - metabolism; Myocytes, Cardiac - metabolism; Myofibroblasts - metabolism; Pathogenesis; Protozoa; RNAi Therapeutics - methods; Tumor necrosis factor-TNF; Up-Regulation; Chagas disease; microRNA; fibrosis; therapeutic target; miR-21; cardiomyopathy
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms22073307

Chagas disease, caused by the parasite Trypanosoma cruzi (T. cruzi), remains a serious public health problem for which there is no effective treatment in the chronic stage. Intense cardiac fibrosis and inflammation are hallmarks of chronic Chagas disease cardiomyopathy (CCC). Previously, we identified upregulation of circulating and cardiac miR-21, a pro-fibrotic microRNA (miRNA), in subjects with CCC. Here, we explored the potential role of miR-21 as a therapeutic target in a model of chronic Chagas disease. PCR array-based 88 microRNA screening was performed in heart samples obtained from C57Bl/6 mice chronically infected with T. cruzi and serum samples collected from CCC patients. MiR-21 was found upregulated in both human and mouse samples, which was corroborated by an in silico analysis of miRNA-mRNA target prediction. In vitro miR-21 functional assays (gain-and loss-of-function) were performed in cardiac fibroblasts, showing upregulation of miR-21 and collagen expression upon transforming growth factor beta 1 (TGFβ1) and T. cruzi stimulation, while miR-21 blockage reduced collagen expression. Finally, treatment of T. cruzi-infected mice with locked nucleic acid (LNA)-anti-miR-21 inhibitor promoted a significant reduction in cardiac fibrosis. Our data suggest that miR-21 is a mediator involved in the pathogenesis of cardiac fibrosis and indicates the pharmacological silencing of miR-21 as a potential therapeutic approach for CCC.