Role of FAK signaling in chagasic cardiac hypertrophy.

Cardiac hypertrophy and dysfunction are a significant complication of chronic Chagas disease, with heart failure, stroke, and sudden death related to disease progression. Thus, understanding the signaling pathways involved in the chagasic cardiac hypertrophy may provide potential targets for pharmacological therapy. Herein, we investigated the implication of focal adhesion kinase (FAK) signaling pathway in triggering hypertrophic phenotype during acute and chronic T. cruzi infection. C57BL/6 mice infected with T. cruzi (Brazil strain) were evaluated for electrocardiographic (ECG) changes, plasma levels of endothelin-1 (ET-1) and activation of signaling pathways involved in cardiac hypertrophy, including FAK and ERK1/2, as well as expression of hypertrophy marker and components of the extracellular matrix in the different stages of T. cruzi infection (60-210 dpi). Heart dysfunction, evidenced by prolonged PR interval and decrease in heart rates in ECG tracing, was associated with high plasma ET-1 level, extracellular matrix remodeling and FAK signaling activation. Upregulation of both FAK tyrosine 397 (FAK-Y397) and serine 910 (FAK-S910) residues phosphorylation as well as ERK1/2 activation, lead to an enhancement of atrial natriuretic peptide gene expression in chronic infection. Our findings highlight FAK-ERK1/2 signaling as a regulator of cardiac hypertrophy in Trypanosoma cruzi infection. Both mechanical stress, induced by cardiac extracellular matrix (ECM) augment and cardiac overload, and ET-1 stimuli orchestrated FAK signaling activation with subsequent activation of the fetal cardiac gene program in the chronic phase of infection, highlighting FAK as an attractive target for Chagas disease therapy.

Regulation of extracellular matrix expression and distribution in Trypanosoma cruzi-infected cardiomyocytes.

Alterations in the extracellular matrix have been observed in the cardiomyopathy of Chagas disease caused by Trypanosoma cruzi infection. However, the mechanism of extracellular matrix regulation in T. cruzi-infected cultured cardiomyocytes (CMs) is unclear. Using confocal laser microscopy, we demonstrated that treatment of these cultures with transforming growth factor beta (TGF-beta) and tumor necrosis factor alpha (TNF-alpha) leads to an enhancement of the fibronectin matrix only in uninfected CMs, while infected myocytes displayed low fibronectin expression. Digital image analysis also revealed low superposition of the fibronectin signal with parasite nests in cytokine treated and untreated cultures. Cytochalasin D treatment resulted in microfilament disarray that induced a disturbance in the fibronectin network of CMs, suggesting that cytoskeleton disruption caused by T. cruzi infection disorganizes the fibronectin matrix. Western blot analysis revealed a 2-fold increase in the fibronectin expression in CM cultures after cytokine treatment, whereas T. cruzi infection significantly reduced fibronectin levels in all conditions. In contrast, no change in the laminin expression was detected after cytokine treatment. Laminin distribution was altered in T. cruzi-infected CMs, with intense laminin labeling only at the cell periphery even after cytokine treatment. Our observations indicate that TGF-beta and TNF-alpha stimulates fibronectin expression only in uninfected cells of the T. cruzi-infected cultures, whereas the cells harboring the parasites display low or no fibronectin fibrils.

Current understanding of the Trypanosoma cruzi-cardiomyocyte interaction.

Trypanosoma cruzi, the etiological agent of Chagas disease, exhibits multiple strategies to ensure its establishment and persistence in the host. Although this parasite has the ability to infect different organs, heart impairment is the most frequent clinical manifestation of the disease. Advances in knowledge of T. cruzi-cardiomyocyte interactions have contributed to a better understanding of the biological events involved in the pathogenesis of Chagas disease. This brief review focuses on the current understanding of molecules involved in T. cruzi-cardiomyocyte recognition, the mechanism of invasion, and on the effect of intracellular development of T. cruzi on the structural organization and molecular response of the target cell.