title: Cardiopathogenic mediators generated by GATA4 signaling upon co-activation with endothelin-1 and Trypanosoma cruzi infection.
abstract: Trypanosoma cruzi (Tc), the etiological agent of Chagas disease, triggers multiple responses in the myocardium, a central organ of infection and pathology in the host. Parasite-driven induction of diverse regulators of cardiovascular function, including the vasoconstrictor endothelin-1 (ET-1), the inducible form of nitric oxide synthase (iNOS) and the B-type natriuretic peptide (BNP), has been linked to the development of severe chagasic cardiomyopathy. Our current goal was to analyze the participation of the zinc finger transcription factor GATA4, critically implicated in pathological cardiac hypertrophic response, in the generation of key mediators involved in the pathogenesis of Tc-elicited heart dysfunction. In this study, we found that the combined effects of Tc and ET-1 on atrial myocytes promoted the protein expression, phosphorylation and DNA-binding activity of GATA4, leading to augmented protein levels of iNOS and increased nitric oxide release. Moreover, Tc- and ET-1-co-activation of cardiomyocytes resulted in enhanced GATA4-dependent secretion of BNP. Accordingly, mice with chronic chagasic cardiomyopathy showed increased expression of GATA4, iNOS and BNP at inflammatory lesions in cardiac muscle. Our findings support a role for the GATA4 signaling pathway in the myocardial production of pathogenic mediators associated with Chagas heart disease, and may help define novel therapeutic targets.
authors.affiliation: Servicio de Parasitología-Chagas, Hospital de Niños "Dr. Ricardo Gutiérrez", Gallo 1330, 1425EFD Ciudad de Buenos Aires, Argentina.
authors.forename: Cristina S
authors.initials: CS
authors.lastname: Rigazio
authors.affiliation: Servicio de Parasitología-Chagas, Hospital de Niños "Dr. Ricardo Gutiérrez", Gallo 1330, 1425EFD Ciudad de Buenos Aires, Argentina.
authors.forename: Matías
authors.initials: M
authors.lastname: Hernández
authors.affiliation: Servicio de Parasitología-Chagas, Hospital de Niños "Dr. Ricardo Gutiérrez", Gallo 1330, 1425EFD Ciudad de Buenos Aires, Argentina. Electronic address: ricardocorral56@hotmail.com.
authors.forename: Ricardo S
authors.initials: RS
authors.lastname: Corral
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D002598:Chagas Cardiomyopathy / Q000473:pathology*; D004195:Disease Models, Animal; D019332:Endothelin-1 / Q000378:metabolism*; D050991:GATA4 Transcription Factor / Q000378:metabolism*; D008807:Mice, Inbred BALB C; D009206:Myocardium / Q000473:pathology*; D020097:Natriuretic Peptide, Brain / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000096:biosynthesis; D015398:Signal Transduction; D014349:Trypanosoma cruzi / Q000472:pathogenicity*
chemical_list: D019332:Endothelin-1; D050991:GATA4 Transcription Factor; C484171:Gata4 protein, mouse; D020097:Natriuretic Peptide, Brain; D009569:Nitric Oxide; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse
keywords: Chagas cardiomyopathy; Endothelin-1; GATA4; Trypanosoma cruzi