| Author | Ferreira, Roberto Rodrigues | |
| Author | Abreu, Rayane da Silva | |
| Author | Pereira, Glaucia Vilar | |
| Author | Degrave, Wim | |
| Author | Meuser-Batista, Marcelo | |
| Author | Ferreira, Nilma Valéria Caldeira | |
| Author | Moreira, Otacílio da Cruz | |
| Author | Gomes, Natália Lins da Silva | |
| Author | Mello de Souza, Elen | |
| Author | Ramos, Isalira P. | |
| Author | Bailly, Sabine | |
| Author | Feige, Jean-Jacques | |
| Author | Lannes-Vieira, Joseli | |
| Author | Araújo-Jorge, Tania C. de | |
| Author | Waghabi, Mariana Caldas | |
| Access date | 2020-03-24T18:42:30Z | |
| Available date | 2020-03-24T18:42:30Z | |
| Document date | 2019 | |
| Citation | FERREIRA, Roberto Rodrigues et al. TGF-β inhibitor therapy decreases fibrosis and stimulates cardiac improvement in a preclinical study of chronic Chagas’ heart disease. PLoS Neglected Tropical Diseases, v. 13, n. 7, p. 1- 27p, July 2019. | pt_BR |
| ISSN | 1935-2727 | pt_BR |
| URI | https://www.arca.fiocruz.br/handle/icict/40490 | |
| Language | eng | pt_BR |
| Publisher | Public Library of Science | pt_BR |
| Rights | open access | |
| Subject in Portuguese | terapia inibidora de TGF-β | pt_BR |
| Subject in Portuguese | Fibrose | pt_BR |
| Subject in Portuguese | Estudo pré-clínico | pt_BR |
| Subject in Portuguese | Cardiopatia chagásica crônica | pt_BR |
| Title | TGF-β inhibitor therapy decreases fibrosis and stimulates cardiac improvement in a pre-clinical study of chronic Chagas' heart disease | pt_BR |
| Type | Article | |
| DOI | 10.1371/journal.pntd.0007602 | |
| Abstract | 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. | pt_BR |
| Affilliation | Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laborato´rio de Genômica Funcional e Bioinformàtica. Rio de Janeiro, RJ, Brasil. | pt_BR |
| Affilliation | Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Genômica Funcional e Bioinformàtica. Rio de Janeiro, RJ, Brasil. | pt_BR |
| Affilliation | Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Biologia das Interações. Rio de Janeiro, RJ, Brasil. | pt_BR |
| Affilliation | Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laborato´rio de Genômica Funcional e Bioinformàtica. Rio de Janeiro, RJ, Brasil. | pt_BR |
| Affilliation | Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Inovações em Terapias, Ensino e Bioprodutos. Rio de Janeiro, RJ, Brasil / Fundação Oswaldo Cruz. Instituto Nacional de Saúde da Mulher, da Criança e do Adolescente Fernandes Figueira. Departamento de Anatomia Patolo´gica e Citopatologia. Rio de Janeiro, RJ, Brasil. | pt_BR |
| Affilliation | Fundação Oswaldo Cruz. Instituto Nacional de Saúde da Mulher, da Criança e do Adolescente Fernandes Figueira. Departamento de Anatomia Patolo´gica e Citopatologia. Rio de Janeiro, RJ, Brasil. | pt_BR |
| Affilliation | Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Biologia Molecular e Doencas Endêmicas. Rio de Janeiro, RJ, Brasil. | pt_BR |
| Affilliation | Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Biologia Molecular e Doencas Endêmicas. Rio de Janeiro, RJ, Brasil. | pt_BR |
| Affilliation | Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Virologia Molecular. Rio de Janeiro, RJ, Brasil. | pt_BR |
| Affilliation | Universidade Federal do Rio de Janeiro. Centro Nacional de Biologia Estrutural e Bioimagem. Rio de Janeiro, RJ, Brasil. | pt_BR |
| Affilliation | Université Grenoble-Alpes, Inserm, CEA. Biology of Cancer and Infection Laboratory. Grenoble, France. | pt_BR |
| Affilliation | Université Grenoble-Alpes, Inserm, CEA. Biology of Cancer and Infection Laboratory. Grenoble, France. | pt_BR |
| Affilliation | Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Biologia das Interações. Rio de Janeiro, RJ, Brasil. | pt_BR |
| Affilliation | Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Inovações em Terapias, Ensino e Bioprodutos. Rio de Janeiro, RJ, Brasil / Fundação Oswaldo Cruz. Instituto Nacional de Saúde da Mulher, da Criança e do Adolescente Fernandes Figueira. Departamento de Anatomia Patolo´gica e Citopatologia. Rio de Janeiro, RJ, Brasil. | pt_BR |
| Affilliation | Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Genômica Funcional e Bioinformàtica. Rio de Janeiro, RJ, Brasil. | pt_BR |
| Subject | Chronic Chagas’ heart disease | pt_BR |
| Subject | TGF-β inhibitor therapy | pt_BR |
| Subject | Fibrosis | pt_BR |
| Subject | Preclinical study | pt_BR |
| e-ISSN | 1935-2735 | |
