Cardiac Chagas Disease: MMPs, TIMPs, Galectins, and TGF-βas Tissue Remodelling Players

Abstract

A century after the discovery of Chagas disease, studies are still needed to establish the complex pathophysiology of this disease. However, it is known that several proteins and molecules are related to the establishment of this disease, its evolution, and the appearance of its different clinical forms. Metalloproteinases and their tissue inhibitors, galectins, and TGF-β are involved in the process of infection and consequently the development of myocarditis, tissue remodeling, and fibrosis upon infection with Trypanosoma cruzi. Thus, considering that the heart is one of the main target organs in Chagas disease, knowledge regarding the mechanisms of action of these molecules is essential to understand how they interact and trigger local and systemic reactions and, consequently, determine whether they contribute to the development of Chagas' heart disease. In this sense, it is believed that the inflammatory microenvironment caused by the infection alters the expression of these proteins favoring progression of the host-parasite cycle and thereby stimulating cardiac tissue remodeling mechanisms and fibrosis. The aim of this review was to gather information on metalloproteinases and their tissue inhibitors, galectins, and TGF-β and discuss how these molecules and their different interrelationships contribute to the development of Chagas' heart disease.

Antigen-Based Nano-Immunotherapy Controls Parasite Persistence, Inflammatory and Oxidative Stress, and Cardiac Fibrosis, the Hallmarks of Chronic Chagas Cardiomyopathy, in A Mouse Model of Trypanosoma cruzi Infection

“…Heart tissue of chronically infected Chagas mice exhibited histological signature of cardiac fibrosis and hypertrophy in this study. Further, MMPs, galectins, and TGF-β, noted to be major tissue remodeling players in human Chagas disease [45], were up-regulated in expression in chronically infected mice in this study. Specifically, MMPs (e.g., MMP2, MMP9) that promote tissue levels of profibrotic mediators and epithelial-to-mesenchymal transition, as well as abnormal epithelial cell migration and other aberrant repair processes, were activated in Chagas mice.…”

Trypanosoma cruzi Induces the PARP1/AP-1 Pathway for Upregulation of Metalloproteinases and Transforming Growth Factor β in Macrophages: Role in Cardiac Fibroblast Differentiation and Fibrosis in Chagas Disease

“…MMP2 and MMP9 are (i) involved in degradation of ECM under normal physiologic and disease conditions ( 18 ), (ii) implicated in cell-to-cell communication independent of their ECM degradation function ( 19 ), and (iii) suggested to dock on the cell surface hyaluronic receptor CD44 to promote cleavage and activation of TGF-β ( 20 ). TGF-β, in turn, downregulates the inflammatory processes and activates cell-proliferative responses ( 18 ). To determine whether MMPs promote Mϕ’s profibrotic response by influencing TGF-β during T. cruzi infection, we incubated RAW Mϕ with T. cruzi in the presence or absence of specific inhibitors of MMP2, MMP9, MMP12, and urokinase-type plasminogen activator (uPA) (which activates MMP2 and MMP9) and monitored release of TGF-β and inflammatory cytokines/chemokines by an enzyme-linked immunosorbent assay (ELISA) at 24 h and 48 h. RAW Mϕ responded to T. cruzi infection with 9- to 10.5-fold, 20- to 27-fold, and 21- to 25-fold increases in TGF-β, TNF-α, and MCP3/CCL7 release, respectively, at 24 h and 48 h post-incubation ( Fig.…”

“…MMP2 and MMP9 promote TGF-␤ activation in macrophages infected with T. cruzi. MMP2 and MMP9 are (i) involved in degradation of ECM under normal physiologic and disease conditions (18), (ii) implicated in cell-to-cell communication independent of their ECM degradation function (19), and (iii) suggested to dock on the cell surface hyaluronic receptor CD44 to promote cleavage and activation of TGF-␤ (20). TGF-␤, in turn, downregulates the inflammatory processes and activates cell-proliferative responses (18).…”

Irreversible Bladder Remodeling Induced by Fibrosis

“…These responses dysregulate fibroblast secretion of matrix metalloproteinases (MMPs) and tissue inhibitors of MMPs (TIMPs) and increase ECM deposition. Prolonged ECM deposition increases the production of TIMPs which are associated with fibrosis and fibrotic changes of the bladder occur [36][37][38]. Moreover, increased levels of TGF-β1 induce fibrosis by stimulating collagen production through binding to serine/threonine ki-nase receptors on the cell surface, cause the phosphorylation of intracellular Smad2/3 transcription factors [39,40].…”