Implication of Transforming Growth Factor–β1 in Chagas Disease Myocardiopathy

Abstract

Cardiac dysfunction with progressive fibrosis is a hallmark of Chagas disease. To evaluate the involvement of transforming growth factor (TGF)-beta1 in this disease, TGF-beta1 levels in patients were measured at 3 stages: asymptomatic indeterminate (IND), cardiac with no or slight heart dysfunction (Card 1), and cardiac with moderate or severe heart dysfunction (Card 2). All patients had significantly higher circulating levels of TGF-beta1 than did healthy persons, and 27% of patients in the Card 1 group had higher TGF-beta1 levels than did patients in the IND group. Immunohistochemical analysis of cardiac biopsy specimens showed strong fibronectin staining in the extracellular matrix and staining for phosphorylated Smad 2 (activation of the TGF-beta1 signaling pathway) in cell nuclei. The higher levels of latent TGF-beta1 observed in patients with myocardiopathy, together with intracellular activation of the TGF-beta1 pathway and tissue fibrosis, suggest that TGF-beta1 plays an important role in Chagas disease. TGF-beta1 may represent a new target for preventive and curative treatments of Chagas disease.

Re-employment of developmental transcription factors in adult heart disease

“…Finally, Smad proteins were further implicated in regulating the cardiac cell lineage by the observation that GATA4 and Smad proteins regulate expression of the Nkx2-5 cardiac enhancer in vivo [140] In the adult, Smad proteins are critically involved in multiple aspects of pathophysiology, including the regulation of cardiac fibrosis. Elevated expression of TGF-β and Smad2, 3 and 4 in the heart was reported after myocardial infarction and in response to cardiomyopathy [141][142][143][144][145][146]. Phosphorylation of Smad2 in cardiac fibroblasts was associated with fibrosis and scar formation, an observation that is consistent with the ability of Smad7 (I-Smad) to inhibit collagen synthesis in the same cells when overexpressed [142,146,147].…”

Pharmacological Inhibition of Transforming Growth Factor β Signaling Decreases Infection and Prevents Heart Damage in Acute Chagas' Disease

“…Several studies have demonstrated that TGF-␤ plays a major role in the establishment and pathogenesis of T. cruzi infection (reviewed in reference 2). TGF-␤ plays a crucial role in three important processes associated with Chagas' disease: (i) stimulation of fibrosis, as demonstrated in Chagas' disease patients and experimental animal models (1,31); (ii) parasite cellular invasion and proliferation (10,18,32,34); (iii) downregulation of cellular and immune mechanisms of parasite control (15,27,28). Moreover, significantly higher circulating levels of TGF-␤1 have been observed in patients with Chagas' disease cardiomyopathy (1).…”

“…Our recent in vitro studies established that the small chemical inhibitor of ALK-5 activity, 4-(5-benzo [1,3]dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)-benzamide (SB-431542) ( Fig. 1) (5), reduces the infection of cardiomyocytes by T. cruzi, inhibits intracellular parasite differentiation, induces parasite apoptosis, and inhibits trypomastigote release (33).…”

SB-431542, a Transforming Growth Factor β Inhibitor, ImpairsTrypanosoma cruziInfection in Cardiomyocytes and Parasite Cycle Completion

“…In this disease, transforming growth factor ␤ (TGF-␤) has been shown to play a crucial role in parasite infection and multiplication and in cardiac fibrosis (2,12,21). It has been demonstrated that antiinflammatory cytokines such as TGF-␤ can promote parasite survival (8,20).…”