Oral administration of GW788388, an inhibitor of transforming growth factor beta signaling, prevents heart fibrosis in Chagas disease.
BACKGROUND: Chagas disease induced by Trypanosoma cruzi (T. cruzi) infection is a major cause of mortality and morbidity affecting the cardiovascular system for which presently available therapies are largely inadequate. Transforming Growth Factor beta (TGFß) has been involved in several regulatory...
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ftdoajarticles:oai:doaj.org/article:d28b1dd732c64d93886243f7a6ba76b3 2023-05-15T15:10:54+02:00 Oral administration of GW788388, an inhibitor of transforming growth factor beta signaling, prevents heart fibrosis in Chagas disease. Fabiane L de Oliveira Tania C Araújo-Jorge Elen M de Souza Gabriel M de Oliveira Wim M Degrave Jean-Jacques Feige Sabine Bailly Mariana C Waghabi 2012-01-01T00:00:00Z https://doi.org/10.1371/journal.pntd.0001696 https://doaj.org/article/d28b1dd732c64d93886243f7a6ba76b3 EN eng Public Library of Science (PLoS) http://europepmc.org/articles/PMC3373641?pdf=render https://doaj.org/toc/1935-2727 https://doaj.org/toc/1935-2735 1935-2727 1935-2735 doi:10.1371/journal.pntd.0001696 https://doaj.org/article/d28b1dd732c64d93886243f7a6ba76b3 PLoS Neglected Tropical Diseases, Vol 6, Iss 6, p e1696 (2012) Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 article 2012 ftdoajarticles https://doi.org/10.1371/journal.pntd.0001696 2022-12-30T23:14:11Z BACKGROUND: Chagas disease induced by Trypanosoma cruzi (T. cruzi) infection is a major cause of mortality and morbidity affecting the cardiovascular system for which presently available therapies are largely inadequate. Transforming Growth Factor beta (TGFß) has been involved in several regulatory steps of T. cruzi invasion and in host tissue fibrosis. GW788388 is a new TGFß type I and type II receptor kinase inhibitor that can be orally administered. In the present work, we studied its effects in vivo during the acute phase of experimental Chagas disease. METHODOLOGY/PRINCIPAL FINDINGS: Male Swiss mice were infected intraperitoneally with 10(4) trypomastigotes of T. cruzi (Y strain) and evaluated clinically. We found that this compound given once 3 days post infection (dpi) significantly decreased parasitemia, increased survival, improved cardiac electrical conduction as measured by PR interval in electrocardiography, and restored connexin43 expression. We could further show that cardiac fibrosis development, evaluated by collagen type I and fibronectin expression, could be inhibited by this compound. Interestingly, we further demonstrated that administration of GW788388 at the end of the acute phase (20 dpi) still significantly increased survival and decreased cardiac fibrosis (evaluated by Masson's trichrome staining and collagen type I expression), in a stage when parasite growth is no more central to this event. CONCLUSION/SIGNIFICANCE: This work confirms that inhibition of TGFß signaling pathway can be considered as a potential alternative strategy for the treatment of the symptomatic cardiomyopathy found in the acute and chronic phases of Chagas disease. Article in Journal/Newspaper Arctic Directory of Open Access Journals: DOAJ Articles Arctic PLoS Neglected Tropical Diseases 6 6 e1696 |
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Directory of Open Access Journals: DOAJ Articles |
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English |
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Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 |
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Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 Fabiane L de Oliveira Tania C Araújo-Jorge Elen M de Souza Gabriel M de Oliveira Wim M Degrave Jean-Jacques Feige Sabine Bailly Mariana C Waghabi Oral administration of GW788388, an inhibitor of transforming growth factor beta signaling, prevents heart fibrosis in Chagas disease. |
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Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 |
description |
BACKGROUND: Chagas disease induced by Trypanosoma cruzi (T. cruzi) infection is a major cause of mortality and morbidity affecting the cardiovascular system for which presently available therapies are largely inadequate. Transforming Growth Factor beta (TGFß) has been involved in several regulatory steps of T. cruzi invasion and in host tissue fibrosis. GW788388 is a new TGFß type I and type II receptor kinase inhibitor that can be orally administered. In the present work, we studied its effects in vivo during the acute phase of experimental Chagas disease. METHODOLOGY/PRINCIPAL FINDINGS: Male Swiss mice were infected intraperitoneally with 10(4) trypomastigotes of T. cruzi (Y strain) and evaluated clinically. We found that this compound given once 3 days post infection (dpi) significantly decreased parasitemia, increased survival, improved cardiac electrical conduction as measured by PR interval in electrocardiography, and restored connexin43 expression. We could further show that cardiac fibrosis development, evaluated by collagen type I and fibronectin expression, could be inhibited by this compound. Interestingly, we further demonstrated that administration of GW788388 at the end of the acute phase (20 dpi) still significantly increased survival and decreased cardiac fibrosis (evaluated by Masson's trichrome staining and collagen type I expression), in a stage when parasite growth is no more central to this event. CONCLUSION/SIGNIFICANCE: This work confirms that inhibition of TGFß signaling pathway can be considered as a potential alternative strategy for the treatment of the symptomatic cardiomyopathy found in the acute and chronic phases of Chagas disease. |
format |
Article in Journal/Newspaper |
author |
Fabiane L de Oliveira Tania C Araújo-Jorge Elen M de Souza Gabriel M de Oliveira Wim M Degrave Jean-Jacques Feige Sabine Bailly Mariana C Waghabi |
author_facet |
Fabiane L de Oliveira Tania C Araújo-Jorge Elen M de Souza Gabriel M de Oliveira Wim M Degrave Jean-Jacques Feige Sabine Bailly Mariana C Waghabi |
author_sort |
Fabiane L de Oliveira |
title |
Oral administration of GW788388, an inhibitor of transforming growth factor beta signaling, prevents heart fibrosis in Chagas disease. |
title_short |
Oral administration of GW788388, an inhibitor of transforming growth factor beta signaling, prevents heart fibrosis in Chagas disease. |
title_full |
Oral administration of GW788388, an inhibitor of transforming growth factor beta signaling, prevents heart fibrosis in Chagas disease. |
title_fullStr |
Oral administration of GW788388, an inhibitor of transforming growth factor beta signaling, prevents heart fibrosis in Chagas disease. |
title_full_unstemmed |
Oral administration of GW788388, an inhibitor of transforming growth factor beta signaling, prevents heart fibrosis in Chagas disease. |
title_sort |
oral administration of gw788388, an inhibitor of transforming growth factor beta signaling, prevents heart fibrosis in chagas disease. |
publisher |
Public Library of Science (PLoS) |
publishDate |
2012 |
url |
https://doi.org/10.1371/journal.pntd.0001696 https://doaj.org/article/d28b1dd732c64d93886243f7a6ba76b3 |
geographic |
Arctic |
geographic_facet |
Arctic |
genre |
Arctic |
genre_facet |
Arctic |
op_source |
PLoS Neglected Tropical Diseases, Vol 6, Iss 6, p e1696 (2012) |
op_relation |
http://europepmc.org/articles/PMC3373641?pdf=render https://doaj.org/toc/1935-2727 https://doaj.org/toc/1935-2735 1935-2727 1935-2735 doi:10.1371/journal.pntd.0001696 https://doaj.org/article/d28b1dd732c64d93886243f7a6ba76b3 |
op_doi |
https://doi.org/10.1371/journal.pntd.0001696 |
container_title |
PLoS Neglected Tropical Diseases |
container_volume |
6 |
container_issue |
6 |
container_start_page |
e1696 |
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1766341832523907072 |