Trypanosoma cruzi infection and endothelin-1 cooperatively activate pathogenic inflammatory pathways in...

Area of Science:

• Cardiovascular Biology
• Infectious Diseases
• Molecular Signaling

Background:

• Chagas' disease, caused by Trypanosoma cruzi, significantly impacts cardiac health.
• Eicosanoids and endothelin-1 (ET-1) are implicated in the progression of chronic chagasic cardiomyopathy.
• Understanding molecular pathways is crucial for managing T. cruzi-induced heart disease.

Purpose of the Study:

• To investigate the role of the Ca(2+)/calcineurin (Cn)/nuclear factor of activated T cells (NFAT) signaling pathway in T. cruzi infection.
• To explore the interplay between T. cruzi, ET-1, and inflammatory mediator production in cardiomyocytes.
• To identify potential therapeutic targets for chagasic cardiomyopathy.

Main Methods:

• Gene expression analysis of key inflammatory mediators (Cox2, Tbxas1, Edn1, Nppa) in T. cruzi-infected mice.
• Stimulation of atrial myocytes and cardiomyocytes with T. cruzi and/or ET-1.
• Assessment of signaling pathway activation (Ca(2+)/Cn/NFAT) and mediator release (eicosanoids, ANP).

Main Results:

• T. cruzi infection upregulated myocardial gene expression of Cox2, Tbxas1, Edn1, and Nppa.
• Cooperative activation of the Ca(2+)/Cn/NFAT pathway by T. cruzi and ET-1 in atrial myocytes.
• Enhanced production of prostaglandins, thromboxane A(2), and atrial natriuretic peptide (ANP) in infected cardiomyocytes.

Conclusions:

• The Ca(2+)/Cn/NFAT cascade plays a key role in T. cruzi-induced inflammatory mediator production in the heart.
• T. cruzi and ET-1 signaling synergistically enhance ANP production, a marker of cardiac dysfunction.
• These findings highlight potential therapeutic strategies targeting this signaling pathway for Chagas' disease.