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 ca2+/calcineurin (cn)/nuclear factor of activated t cells (nfat) signaling pathway in atrial myocytes,leading to cox-2 protein expression and increased eicosanoid (prostaglandins e2 and f2α,thromboxane a2) 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 ca2+/cn/nfat cascade in t. cruzi-mediated myocardial production of inflammatory mediators and may help define novel therapeutic targets. © 2013 corral et al.