Pharmacological inhibition of transforming growth factor beta signaling decreases infection and prevents heart damage in acute Chagas' disease.
Chagas' disease induced by Trypanosoma cruzi infection is an important cause of mortality and morbidity affecting the cardiovascular system for which presently available therapies are largely inadequate. We previously reported that transforming growth factor beta (TGF-beta) is implicated in several regulatory aspects of T. cruzi invasion and growth and in host tissue fibrosis. This prompted us to evaluate the therapeutic action of an inhibitor of TGF-beta signaling (SB-431542) administered during the acute phase of experimental Chagas' disease. Male Swiss mice were infected intraperitoneally with 10(4) trypomastigotes of T. cruzi (Y strain) and evaluated clinically for the following 30 days. SB-431542 treatment significantly reduced mortality and decreased parasitemia. Electrocardiography showed that SB-431542 treatment was effective in protecting the cardiac conduction system. By 14 day postinfection, enzymatic biomarkers of tissue damage indicated that muscle injury was decreased by SB-431542 treatment, with significantly lower blood levels of aspartate aminotransferase and creatine kinase. In conclusion, inhibition of TGF-beta signaling in vivo appears to potently decrease T. cruzi infection and to prevent heart damage in a preclinical mouse model. This suggests that this class of molecules may represent a new therapeutic agent for acute and chronic Chagas' disease that warrants further clinical exploration.
Waghabi
Mariana C
MC
Laboratório de Inovações em Terapias, Ensino e Bioprodutos, Instituto Oswaldo Cruz, Av. Brasil 4365, Rio de Janeiro, RJ 20045-900, Brazil.
de Souza
Elen M
EM
de Oliveira
Gabriel M
GM
Keramidas
Michelle
M
Feige
Jean-Jacques
JJ
Araújo-Jorge
Tania C
TC
Bailly
Sabine
S
D000818:Animals; D001549:Benzamides / Q000627:therapeutic use*; D001919:Bradycardia / Q000517:prevention & control; D002598:Chagas Cardiomyopathy / Q000517:prevention & control*; D014355:Chagas Disease / Q000188:drug therapy*; D004149:Dioxoles / Q000627:therapeutic use*; D008297:Male; D051379:Mice; D009206:Myocardium / Q000473:pathology; D018512:Parasitemia / Q000188:drug therapy; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000502:physiology; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000037:antagonists & inhibitors* / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects*
C459179:4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide; D001549:Benzamides; D004149:Dioxoles; D018125:Receptors, Transforming Growth Factor beta; D017346:Protein Serine-Threonine Kinases; D000077293:Receptor, Transforming Growth Factor-beta Type I