title: Trypanosoma cruzi infection and endothelin-1 cooperatively activate pathogenic inflammatory pathways in cardiomyocytes.
abstract: Trypanosoma cruzi, the causative agent of Chagas' disease, induces multiple responses in the heart, a critical organ of infection and pathology in the host. Among diverse factors, eicosanoids and the vasoactive peptide endothelin-1 (ET-1) have been implicated in the pathogenesis of chronic chagasic cardiomyopathy. In the present study, we found that T. cruzi infection in mice induces myocardial gene expression of cyclooxygenase-2 (Cox2) and thromboxane synthase (Tbxas1) as well as endothelin-1 (Edn1) and atrial natriuretic peptide (Nppa). T. cruzi infection and ET-1 cooperatively activated the Ca(2+)/calcineurin (Cn)/nuclear factor of activated T cells (NFAT) signaling pathway in atrial myocytes, leading to COX-2 protein expression and increased eicosanoid (prostaglandins E(2) and F(2α), thromboxane A(2)) release. Moreover, T. cruzi infection of ET-1-stimulated cardiomyocytes resulted in significantly enhanced production of atrial natriuretic peptide (ANP), a prognostic marker for impairment in cardiac function of chagasic patients. Our findings support an important role for the Ca(2+)/Cn/NFAT cascade in T. cruzi-mediated myocardial production of inflammatory mediators and may help define novel therapeutic targets.
authors: Servicio de Parasitología-Chagas, Hospital de Niños Ricardo Gutiérrez, Buenos Aires, Argentina. ricardocorral56@hotmail.com
authors: Ricardo S
authors: RS
authors: Corral
authors: Néstor A
authors: NA
authors: Guerrero
authors: Henar
authors: H
authors: Cuervo
authors: Núria
authors: N
authors: Gironès
authors: Manuel
authors: M
authors: Fresno
mesh_terms: D000818:Animals; D009320:Atrial Natriuretic Factor; D019703:Calcineurin / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000096:biosynthesis; D019332:Endothelin-1 / Q000096:biosynthesis*; D020869:Gene Expression Profiling; D007249:Inflammation; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009000:Monocytes / Q000276:immunology / Q000469:parasitology; D032383:Myocytes, Cardiac / Q000276:immunology* / Q000469:parasitology*; D050778:NFATC Transcription Factors / Q000378:metabolism; D020098:Natriuretic Peptide, C-Type / Q000096:biosynthesis; D011498:Protein Precursors / Q000096:biosynthesis; D015398:Signal Transduction; D013930:Thromboxane-A Synthase / Q000096:biosynthesis; D014349:Trypanosoma cruzi / Q000276:immunology* / Q000472:pathogenicity*
chemical_list: D019332:Endothelin-1; D050778:NFATC Transcription Factors; C431578:Nppa protein, mouse; D011498:Protein Precursors; D020098:Natriuretic Peptide, C-Type; D009320:Atrial Natriuretic Factor; D051546:Cyclooxygenase 2; D019703:Calcineurin; D013930:Thromboxane-A Synthase; D002118:Calcium