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.

Author Summary

Chronic cardiomyopathy is the most common and severe manifestation of human Chagas' disease, caused by the protozoan parasite Trypanosoma cruzi. Among diverse inflammation-promoting moieties, eicosanoids and the vasoactive peptide endothelin-1 (ET-1) have been implicated in its pathogenesis. Nevertheless, the link between these two factors has not yet been identified. In the present study, we found that T. cruzi infection induces gene expression of ET-1 and eicosanoid-forming enzymes in the heart of infected mice. We also demonstrated that HL-1 atrial myocytes respond to ET-1 stimulus and T. cruzi infection by induction of cyclooxygenase-2 through activation of the Ca ²⁺/calcineurin/NFAT intracellular signaling pathway. Moreover, the cooperation between T. cruzi and ET-1 leads to overproduction of eicosanoids (prostaglandins E ₂ and F _2α, thromboxane A ₂) and the pro-hypertrophic atrial natriuretic peptide. Our results support an important role for NFAT in T. cruzi plus ET-1-dependent induction of key agents of pathogenesis in chronic chagasic cardiomyopathy. Identification of the Ca ²⁺/calcineurin/NFAT cascade as mediator of cardiovascular pathology in Chagas' disease advances our understanding of host-parasite interrelationship and may help define novel potential targets for therapeutic interventions to ameliorate or prevent cardiomyopathy during chronic T. cruzi infection.