Pirfenidone Prevents Heart Fibrosis during Chronic Chagas Disease Cardiomyopathy.
Int J Mol Sci
; 25(13)2024 Jul 03.
Article
em En
| MEDLINE
| ID: mdl-39000409
ABSTRACT
Cardiac fibrosis is a severe outcome of Chagas disease (CD), caused by the protozoan Trypanosoma cruzi. Clinical evidence revealed a correlation between fibrosis levels with impaired cardiac performance in CD patients. Therefore, we sought to analyze the effect of inhibitors of TGF-ß (pirfenidone), p38-MAPK (losmapimod) and c-Jun (SP600125) on the modulation of collagen deposition in cardiac fibroblasts (CF) and in vivo models of T. cruzi chronic infection. Sirius Red/Fast Green dye was used to quantify both collagen expression and total protein amount, assessing cytotoxicity. The compounds were also used to treat C57/Bl6 mice chronically infected with T. cruzi, Brazil strain. We identified an anti-fibrotic effect in vitro for pirfenidone (TGF-ß inhibitor, IC50 114.3 µM), losmapimod (p38 inhibitor, IC50 17.6 µM) and SP600125 (c-Jun inhibitor, IC50 3.9 µM). This effect was independent of CF proliferation since these compounds do not affect T. cruzi-induced host cell multiplication as measured by BrdU incorporation. Assays of chronic infection of mice with T. cruzi have shown a reduction in heart collagen by pirfenidone. These results propose a novel approach to fibrosis therapy in CD, with the prospect of repurposing pirfenidone to prevent the onset of ECM accumulation in the hearts of the patients.
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Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Piridonas
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Fibrose
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Cardiomiopatia Chagásica
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Camundongos Endogâmicos C57BL
Limite:
Animals
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Humans
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Male
Idioma:
En
Revista:
Int J Mol Sci
Ano de publicação:
2024
Tipo de documento:
Article