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 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.

Longistatin in tick saliva blocks advanced glycation end-product receptor activation

“…RAGE ligands (e.g., endogenous alarmin S100 proteins) have been shown to increase Cox2 expression in RAGE-related inflammatory settings (43). In parasitic diseases, COX2 has also been shown to be upregulated and predicted to have an impact (44). On the other hand, MCP-5, known as an MCP-1-related chemokine, specifically attracts monocytes and eosinophils.…”

Cardioprotective actions of curcumin on the pathogenic NFAT/COX-2/prostaglandin E2 pathway induced during Trypanosoma cruzi infection

“…Along this line, we previously found that T. cruzi infection and endothelin-1 (ET-1) cooperatively activate the Ca 2+ /calcineurin/NFAT cascade in atrial myocytes, leading to cyclooxygenase type 2 (COX-2) induction and increased release of inflammatory mediators (Corral et al, 2013). As the antiinflammatory actions of Cur largely stem from its ability to target key molecules (enzymes, cytokines, transcription factors) implicated in the etiology of different malignancies (Deguchi, 2015), we aimed to investigate whether Cur treatment of ET-1-stimulated and T. cruzi-infected cardiac cells could interfere with this pathway responsible for the production of inflammatory effectors relevant to the pathogenesis of Chagas heart disease.…”

“…Mouse HL-1 cardiomyocytes were plated onto gelatin/fibronectin precoated flasks and cultured at 37ºC, 5% CO 2 in Claycomb medium (SigmaAldrich) supplemented with 10% fetal calf serum (FCS), 100 U/ml penicillin, 100 μg/ml streptomycin and 2 mM L-glutamine as previously described (Corral et al, 2013). HL-1 cells were treated with 0.3 nM endotoxin-free ET-1 (Sigma-Aldrich) for 2 h and then infected for 3 h or 24 h with T. cruzi trypomastigotes (cell:parasite ratio 1:5), RA strain, in the presence and absence of Cur (0-13.5-27.0 μM).…”

Inhibition of Cyclooxygenase-1 and Cyclooxygenase-2 Impairs Trypanosoma cruzi Entry into Cardiac Cells and Promotes Differential Modulation of the Inflammatory Response

“…Although T. cruzi trypomastigotes are broadly dispersed among many different organs in the mammalian host, cardiac tissue is an important target for this parasite, and the T. cruzicardiomyocyte interaction has been the subject of intense investigation (4)(5)(6)(7).…”