Journal Article

TGF-β inhibitor therapy decreases fibrosis and stimulates cardiac improvement in a pre-clinical study of chronic Chagas’ heart disease

Feige, Jean-Jacques, da Cruz Moreira, Otacílio, Abreu, Rayane da Silva, Waghabi, Mariana Caldas, Bailly, Sabine, Lannes-Vieira, Joseli, Vilar-Pereira, Glaucia, Ramos, Isalira P., de Araújo-Jorge, Tania C., Ferreira, Roberto Rodrigues, Degrave, Wim, Ferreira, Nilma Valéria Caldeira, da Silva Gomes, Natália Lins, Mello de Souza, Elen, Meuser-Batista, Marcelo

2019

Overview

TGF-β involvement in Chagas disease cardiomyopathy has been clearly demonstrated. The TGF-β signaling pathway is activated in the cardiac tissue of chronic phase patients and is associated with an increase in extracellular matrix protein expression. The aim of this study was to investigate the effect of GW788388, a selective inhibitor of TβR1/ALK5, on cardiac function in an experimental model of chronic Chagas' heart disease. To this end, C57BL/6 mice were infected with Trypanosoma cruzi (102 parasites from the Colombian strain) and treated orally with 3mg/kg GW788388 starting at 120 days post-infection (dpi), when 100% of the infected mice show cardiac damage, and following three distinct treatment schedules: i) single dose; ii) one dose per week; or iii) three doses per week during 30 days. The treatment with GW788388 improved several cardiac parameters: reduced the prolonged PR and QTc intervals, increased heart rate, and reversed sinus arrhythmia, and atrial and atrioventricular conduction disorders. At 180 dpi, 30 days after treatment interruption, the GW3x-treated group remained in a better cardiac functional condition. Further, GW788388 treatment reversed the loss of connexin-43 enriched intercellular plaques and reduced fibrosis of the cardiac tissue. Inhibition of the TGF-β signaling pathway reduced TGF-β/pSmad2/3, increased MMP-9 and Sca-1, reduced TIMP-1/TIMP-2/TIMP-4, and partially restored GATA-6 and Tbox-5 transcription, supporting cardiac recovery. Moreover, GW788388 administration did not modify cardiac parasite load during the infection but reduced the migration of CD3+ cells to the heart tissue. Altogether, our data suggested that the single dose schedule was not as effective as the others and treatment three times per week during 30 days seems to be the most effective strategy. The therapeutic effects of GW788388 are promising and suggest a new possibility to treat cardiac fibrosis in the chronic phase of Chagas' heart disease by TGF-β inhibitors.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Animals / Arrhythmia / Benzamides - therapeutic use / Biology and Life Sciences / Cardiac arrhythmia / Cardiomyocytes / Cardiomyopathy / Cardiovascular disease / Cardiovascular diseases / CD3 antigen / Cell migration / Chagas Cardiomyopathy - drug therapy / Chagas Cardiomyopathy - parasitology / Chagas Cardiomyopathy - pathology / Chagas disease / Chronic Disease / Conduction / Connexin 43 / Connexin 43 - metabolism / Coronary artery disease / Disease Models, Animal / Dosage / Extracellular / Extracellular matrix / Female / Fibrosis / Fibrosis - drug therapy / Gelatinase B / Heart / Heart - drug effects / Heart - parasitology / Heart Conduction System - drug effects / Heart diseases / Heart rate / Infections / Inhibitors / Laboratories / Life Sciences / Matrix protein / Medicine and Health Sciences / Mice / Mice, Inbred C57BL / Parasite Load / Parasites / Plaques / Protozoa / Pyrazoles - therapeutic use / Research and Analysis Methods / Schedules / Signal transduction / Signaling / Strain / Therapy / Tissue / Tissue inhibitor of metalloproteinase 1 / Tissue inhibitor of metalloproteinase 2 / Tissue inhibitor of metalloproteinase 4 / Tissues / Transcription / Transforming Growth Factor beta - antagonists & inhibitors / Tropical diseases / Trypanocidal Agents - therapeutic use / Trypanosoma cruzi - drug effects / Vector-borne diseases