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  • Introduction Chronic cardiomyopathy is the most frequent and

    2019-07-24

    Introduction Chronic cardiomyopathy is the most frequent and severe manifestation of Chagas disease, triggered by infection with the protozoan parasite Trypanosoma cruzi. It affects approximately one-third of T. cruzi-infected patients, typically years or decades after the initial exposure [1]. Multiple mechanisms have been suggested to explain the pathogenesis of parasite-elicited cardiomyopathy, including pathogen persistence, exacerbated inflammatory response, autoimmunity, microvascular disorders and/or neurogenic disturbances [2]. This complex process still remains incompletely understood, but it is now clear that prolonged inflammation due to incessant cardiac parasitism provokes serious damage to the conduction system and myocardium [3], [4]. A selective CD8+ T cell trafficking towards the target organ is driven by a mosaic of local chemoattractant agents including adhesion molecules, extracellular matrix components, and pro-inflammatory cytokines and chemokines, particularly CCL2, CCL3, CCL5, CXCL9 and CXCL10 [5]. Focal myocarditis becomes more intense as the disease progresses to severe clinical stages. In advanced cases, the loss of cardiomyocytes and their substitution by fibrotic tissue lead to disruption of muscle fibers and malfunctioning of the electrophysiologic sincitia. Cardiovascular alterations predispose the infected patient to heart failure and ventricular arrhythmias, with increased risk of premature death [6]. Among other cardiopathogenic factors, T. cruzi infection induces the production of several inflammatory enzymes, including matrix metalloproteinases (MMPs). This protein superfamily comprises a panel of zinc-dependent endopeptidases that are classified into families according to their substrate specificity [7]. The USP7/USP47 inhibitor and activities of MMPs are strictly controlled under normal circumstances, but often become activated in the development of diverse pathologies, such as neoplasia, arthritis, and neurodegenerative and cardiovascular disorders [8], [9]. In addition, overexpression of MMPs has been associated with tissue remodeling during infections with protozoan parasites [10]. In experimental T. cruzi infection, increased levels of the gelatinases MMP-2 and MMP-9 have been suggested to contribute to acute myocarditis by favoring leukocyte infiltration and modulating immunity [11], [12]. Moreover, enhanced MMP-2 and MMP-9 expression has been linked to the cardiac clinical form in chronic Chagas patients. Both enzymes have been postulated as potentially useful biomarkers of the progression to severe T. cruzi cardiomyopathy, as well as promising therapeutic targets [13], [14], [15]. Regarding the control of gelatinase levels, the cytokine and cell attachment phosphoprotein osteopontin (OPN) has been implicated in the upregulation of MMP-2 expression and activity in tumor cells [16], and also in orchestrating inflammation against T. cruzi [17]. In the present study, we investigated the role of endogenous OPN as a modulator of myocardial CCL5 and MMP-2, as well as its pathological impact in a murine model of chronic Chagas heart disease.
    Material and methods
    Results
    Discussion MMPs have been largely related to development of myocarditis caused by prolonged infections of diverse etiology [33], [34], [35]. In particular, increased MMP-2 activity has been implicated in the transition from hypertrophy to heart failure, whereas MMP-9 has been linked to chronic inflammatory cardiomyopathy via activation of endothelial and myocyte apoptotic pathways rather than promoting fibrosis [36], [37], [38]. With regard to human chronic Chagas heart disease, MMP-2 and MMP-9 have been characterized as useful biomarkers for detecting the advent and progression of cardiomyopathy, even with predictive potential on mortality [13], [15], [39], [40], [41], [42]. Of note, the MMP-2/MMP-9 ratio was found to reach significantly higher values in T. cruzi-infected patients displaying ECG abnormalities [43]. Moreover, MMP-2 overexpression and enhanced activity appear to rise progressively with increasing complexity of left ventricular dysfunction and cardiac hypertrophy in individuals with advanced-stage infection by this parasite [14], [15].