Trypanosoma cruzi Infection and Endothelin-1 Cooperatively Activate Pathogenic Inflammatory Pathways in Cardiomyocytes

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.