The TGF-β Pathway as an Emerging Target for Chagas Disease Therapy

Abstract

Transforming growth factor-β (TGF-β) influences the development of myocardiopathy in Chagas disease through regulation of (i) parasite invasion of heart cells, (ii) an intracellular parasite cycle, (iii) inflammation and immune response, (iv) heart fibrosis and remodeling, and (v) gap junction modulation and heart conduction. In this review, we discuss the rationale for developing TGF-β signaling-interfering therapies as adjuvant approaches for the management of the cardiac alterations of Chagas disease-affected patients.

Differential cytokine profiling in Chagasic patients according to their arrhythmogenic-status

“…Infliximab, an TNF blocker, could reduce the frequency of mice afflicted by arrhythmias and second degree atrioventricular blocks in an experimental model of chronic Chagas disease [23]. Gene expression of pro-inflammatory factors associated to inflammatory response (IFN-γ, transcription factor T-bet, GATA-3; FoxP3 and CTLA-4; IL-17 and IL-18) were upregulated in heart samples of chronic Chagasic patients [24] and its inflammatory environment has been reported as inductor of gene expression related with heart failure [25] and gap junction dysfunction during Chagas disease [26], possibly explaining this fact the electrical disturbances observed in patients. Interestingly and closely related with our results, IL-2 was able to induce in vitro the expression of SCN3B and sodium current density [27], increasing of atrial action potential duration [28] and IL-2 has been linked to prognosis for atrial fibrillation in patients [29].…”

Developments in the management of Chagas cardiomyopathy

“…In different cell types, TGF-β contributes to tissue repair and remodeling [34] and in cell differentiation to myofibroblasts. [35] TGF-β also induces connective tissue growth factor and is critical for the preservation of the matrix by suppressing the activity of matrix metalloproteinases and inducing the production of protease inhibitors. [35] Moreover, TGF-β modulates the cardiac myocyte phenotype and triggers hypertrophic effects.…”

“…[35] TGF-β also induces connective tissue growth factor and is critical for the preservation of the matrix by suppressing the activity of matrix metalloproteinases and inducing the production of protease inhibitors. [35] Moreover, TGF-β modulates the cardiac myocyte phenotype and triggers hypertrophic effects. [35,36] In the myocardium of Chagas disease patients, there are increased levels of TGF-β and other growth factors, such as granulocyte-macrophage-colony-stimulating factor and platelet-derived growth factor [37] that may mediate fibrosis.…”

“…[35] Moreover, TGF-β modulates the cardiac myocyte phenotype and triggers hypertrophic effects. [35,36] In the myocardium of Chagas disease patients, there are increased levels of TGF-β and other growth factors, such as granulocyte-macrophage-colony-stimulating factor and platelet-derived growth factor [37] that may mediate fibrosis. In a retrospective study of 54 Chagas disease patients, TGF-β1 was independently associated with all-cause mortality and hospitalization due to heart failure or cardiac arrhythmias.…”

Dab2 attenuates brain injury in APP/PS1 mice via targeting transforming growth factor-beta/SMAD signaling

“…Transforming growth factor-ββ exhibits a variety of biological effects, and participates widely in diverse pathophysiological processes, including cell apoptosis and proliferation, stem cell differentiation and embryonic development, extracellular matrix formation, wound repair and inflammatory reactions[9101112]. Transforming growth factor-β1 is the most important subtype in the central nervous system, being mainly expressed in neurons and microglia, and its level can be increased by stress after nerve injury.…”