TGF-β inhibitor therapy decreases fibrosis and stimulates cardiac improvement in a pre-clinical study of chronic Chagas' heart disease.
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 effec...
Published in: | PLOS Neglected Tropical Diseases |
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ftdoajarticles:oai:doaj.org/article:3736842f86a242e598ff553363a576b7 2023-05-15T15:18:28+02:00 TGF-β inhibitor therapy decreases fibrosis and stimulates cardiac improvement in a pre-clinical study of chronic Chagas' heart disease. Roberto Rodrigues Ferreira Rayane da Silva Abreu Glaucia Vilar-Pereira Wim Degrave Marcelo Meuser-Batista Nilma Valéria Caldeira Ferreira Otacílio da Cruz Moreira Natália Lins da Silva Gomes Elen Mello de Souza Isalira P Ramos Sabine Bailly Jean-Jacques Feige Joseli Lannes-Vieira Tania C de Araújo-Jorge Mariana Caldas Waghabi 2019-07-01T00:00:00Z https://doi.org/10.1371/journal.pntd.0007602 https://doaj.org/article/3736842f86a242e598ff553363a576b7 EN eng Public Library of Science (PLoS) https://doi.org/10.1371/journal.pntd.0007602 https://doaj.org/toc/1935-2727 https://doaj.org/toc/1935-2735 1935-2727 1935-2735 doi:10.1371/journal.pntd.0007602 https://doaj.org/article/3736842f86a242e598ff553363a576b7 PLoS Neglected Tropical Diseases, Vol 13, Iss 7, p e0007602 (2019) Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 article 2019 ftdoajarticles https://doi.org/10.1371/journal.pntd.0007602 2022-12-31T11:45:09Z 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. Article in Journal/Newspaper Arctic Directory of Open Access Journals: DOAJ Articles Arctic Gata ENVELOPE(-19.702,-19.702,63.540,63.540) PLOS Neglected Tropical Diseases 13 7 e0007602 |
institution |
Open Polar |
collection |
Directory of Open Access Journals: DOAJ Articles |
op_collection_id |
ftdoajarticles |
language |
English |
topic |
Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 |
spellingShingle |
Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 Roberto Rodrigues Ferreira Rayane da Silva Abreu Glaucia Vilar-Pereira Wim Degrave Marcelo Meuser-Batista Nilma Valéria Caldeira Ferreira Otacílio da Cruz Moreira Natália Lins da Silva Gomes Elen Mello de Souza Isalira P Ramos Sabine Bailly Jean-Jacques Feige Joseli Lannes-Vieira Tania C de Araújo-Jorge Mariana Caldas Waghabi TGF-β inhibitor therapy decreases fibrosis and stimulates cardiac improvement in a pre-clinical study of chronic Chagas' heart disease. |
topic_facet |
Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 |
description |
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. |
format |
Article in Journal/Newspaper |
author |
Roberto Rodrigues Ferreira Rayane da Silva Abreu Glaucia Vilar-Pereira Wim Degrave Marcelo Meuser-Batista Nilma Valéria Caldeira Ferreira Otacílio da Cruz Moreira Natália Lins da Silva Gomes Elen Mello de Souza Isalira P Ramos Sabine Bailly Jean-Jacques Feige Joseli Lannes-Vieira Tania C de Araújo-Jorge Mariana Caldas Waghabi |
author_facet |
Roberto Rodrigues Ferreira Rayane da Silva Abreu Glaucia Vilar-Pereira Wim Degrave Marcelo Meuser-Batista Nilma Valéria Caldeira Ferreira Otacílio da Cruz Moreira Natália Lins da Silva Gomes Elen Mello de Souza Isalira P Ramos Sabine Bailly Jean-Jacques Feige Joseli Lannes-Vieira Tania C de Araújo-Jorge Mariana Caldas Waghabi |
author_sort |
Roberto Rodrigues Ferreira |
title |
TGF-β inhibitor therapy decreases fibrosis and stimulates cardiac improvement in a pre-clinical study of chronic Chagas' heart disease. |
title_short |
TGF-β inhibitor therapy decreases fibrosis and stimulates cardiac improvement in a pre-clinical study of chronic Chagas' heart disease. |
title_full |
TGF-β inhibitor therapy decreases fibrosis and stimulates cardiac improvement in a pre-clinical study of chronic Chagas' heart disease. |
title_fullStr |
TGF-β inhibitor therapy decreases fibrosis and stimulates cardiac improvement in a pre-clinical study of chronic Chagas' heart disease. |
title_full_unstemmed |
TGF-β inhibitor therapy decreases fibrosis and stimulates cardiac improvement in a pre-clinical study of chronic Chagas' heart disease. |
title_sort |
tgf-β inhibitor therapy decreases fibrosis and stimulates cardiac improvement in a pre-clinical study of chronic chagas' heart disease. |
publisher |
Public Library of Science (PLoS) |
publishDate |
2019 |
url |
https://doi.org/10.1371/journal.pntd.0007602 https://doaj.org/article/3736842f86a242e598ff553363a576b7 |
long_lat |
ENVELOPE(-19.702,-19.702,63.540,63.540) |
geographic |
Arctic Gata |
geographic_facet |
Arctic Gata |
genre |
Arctic |
genre_facet |
Arctic |
op_source |
PLoS Neglected Tropical Diseases, Vol 13, Iss 7, p e0007602 (2019) |
op_relation |
https://doi.org/10.1371/journal.pntd.0007602 https://doaj.org/toc/1935-2727 https://doaj.org/toc/1935-2735 1935-2727 1935-2735 doi:10.1371/journal.pntd.0007602 https://doaj.org/article/3736842f86a242e598ff553363a576b7 |
op_doi |
https://doi.org/10.1371/journal.pntd.0007602 |
container_title |
PLOS Neglected Tropical Diseases |
container_volume |
13 |
container_issue |
7 |
container_start_page |
e0007602 |
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1766348660826701824 |