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https://www.arca.fiocruz.br/handle/icict/46757
THERAPEUTIC MIR-21 SILENCING REDUCES CARDIAC FIBROSIS AND MODULATES INFLAMMATORY RESPONSE IN CHRONIC CHAGAS DISEASE
Author
Nonaka, Carolina Kymie Vasques
Sampaio, Gabriela Louise
França, Luciana de Aragão
Cavalcante, Bruno Raphael
Silva, Katia Nunes
Cunha, Antonio Ricardo Khouri
Torres, Felipe Guimarães
Meira, Cassio Santana
Santos, Emanuelle de Souza
Macedo, Carolina Thé
Paredes, Bruno Diaz
Rocha, Vinicius Pinto Costa
Rogatto, Silvia Regina
Santos, Ricardo Ribeiro dos
Souza, Bruno Solano de Freitas
Soares, Milena Botelho Pereira
Sampaio, Gabriela Louise
França, Luciana de Aragão
Cavalcante, Bruno Raphael
Silva, Katia Nunes
Cunha, Antonio Ricardo Khouri
Torres, Felipe Guimarães
Meira, Cassio Santana
Santos, Emanuelle de Souza
Macedo, Carolina Thé
Paredes, Bruno Diaz
Rocha, Vinicius Pinto Costa
Rogatto, Silvia Regina
Santos, Ricardo Ribeiro dos
Souza, Bruno Solano de Freitas
Soares, Milena Botelho Pereira
Affilliation
"Múltipla ver em Notas"
Abstract
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 (gainand
loss-of-function) were performed in cardiac fibroblasts, showing upregulation of miR-21 and
collagen expression upon transforming growth factor beta 1 (TGF 1) 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.
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