Pirfenidone Prevents Heart Fibrosis during Chronic Chagas Disease Cardiomyopathy

• Published in: International journal of molecular sciences 2024-07, Vol.25 (13), p.7302
• Main Authors: Silva, Tatiana Araújo, Thomas, Diane, Siqueira-Neto, Jair L, Calvet, Claudia Magalhaes
• Format: Article
• Language: English
• Subjects: Animals; Anthracenes; Cardiomyocytes; Cardiomyopathy; Chagas Cardiomyopathy - drug therapy; Chagas Cardiomyopathy - metabolism; Chagas Cardiomyopathy - parasitology; Chagas Cardiomyopathy - pathology; Chagas disease; Chronic Disease; Clinical trials; Collagen; Collagen - metabolism; Cytokines; Disease Models, Animal; Ejection fraction; Extracellular matrix; Fibroblasts; Fibroblasts - drug effects; Fibroblasts - metabolism; Fibroblasts - parasitology; Fibrosis; Heart attacks; Heart failure; heart fibrosis; Humans; Infections; Inflammation; Kinases; Male; Mice; Mice, Inbred C57BL; Mortality; Myocardium - metabolism; Myocardium - pathology; p38 Mitogen-Activated Protein Kinases - metabolism; Parasites; pirfenidone; Protozoa; Pyridones - pharmacology; Pyridones - therapeutic use; Transforming Growth Factor beta - metabolism; Trypanosoma cruzi - drug effects; Tumor necrosis factor-TNF
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms25137302

Cardiac fibrosis is a severe outcome of Chagas disease (CD), caused by the protozoan . 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-β (pirfenidone), p38-MAPK (losmapimod) and c-Jun (SP600125) on the modulation of collagen deposition in cardiac fibroblasts (CF) and in vivo models of 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 , Brazil strain. We identified an anti-fibrotic effect in vitro for pirfenidone (TGF-β 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 -induced host cell multiplication as measured by BrdU incorporation. Assays of chronic infection of mice with 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.