Abstract
Trypanosoma cruzi infection induces progressive cardiac inflammation that leads to fibrosis and modifications in the heart architecture and functionality. Statins, such as 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase inhibitors, have been studied due to their pleiotropic roles in modulating the inflammatory response. Our goal was to evaluate the effects of simvastatin on the cardiac inflammatory process using a cardiotropic strain of T. cruzi in a murine model of Chagas cardiomyopathy. C57BL/6 mice were infected with 500 trypomastigotes of the Colombian strain of T. cruzi and treated with an oral dose of simvastatin (20 mg/Kg/day) for one month and inflammatory and morphometric parameters were subsequently evaluated in the serum and in the heart, respectively. Simvastatin reduced the total cholesterol and inflammatory mediators (interferon-gamma, tumour necrosis factor-alpha, CCL2 and CCL5) in the serum and in the heart tissue at 30 days post-infection. Additionally, a proportional reduction in heart weight and inflammatory infiltration was observed. Simvastatin also reduced epimastigote proliferation in a dose-dependent manner in vitro and was able to reduce blood trypomastigotes and heart amastigote nests during the acute phase of Chagas disease in vivo. Based on these data, we conclude that simvastatin exerts a modulatory effect on the inflammatory mediators that are elicited by the Colombian strain of T. cruzi and ameliorates the heart damage that is observed in a murine model of Chagas disease.
Highlights
Chagas cardiomyopathy (CC) is a chronic clinical manifestation that is caused by the protozoan Trypanosoma cruzi
Some studies have suggested that the specific statin simvastatin may affect immune-mediated inflammation because of the documented ability of this statin to reduce the adhesion of inflammatory cells to the endothelium, inhibit leukocyte adhesion by direct interactions with the leukocyte-function antigen-1 and modulate the expression of the integrin dimer CD11b on monocytes
A new set of mice were divided into the following groups: (i) 10 mice infected with T. cruzi receiving vehicle, (ii) 10 mice infected with T. cruzi and treated with simvastatin (20 mg/kg), (iii) 10 non-infected mice receiving vehicle only and (iv) 10 non-infected mice treated with simvastatin (20 mg/kg)
Summary
Chagas cardiomyopathy (CC) is a chronic clinical manifestation that is caused by the protozoan Trypanosoma cruzi. This protozoan induces persistent inflammation comprised of neutrophils, macrophages, CD4+ and CD8+ T cells (Reis et al 1993, Brener & Gazzinelli 1997) that culminates in myocarditis, fibrosis and changes in the heart architecture and functionality This illness, which affects approximately 10 million individuals in Latin America, is characterised by persistent inflammatory remodelling of the heart tissue and is becoming the most common form of progressive, non-ischaemic heart disease worldwide (Prata 2001, WHO 2010). Both systemically and at chronic inflammatory foci, inflammatory cells release inflammatory cytokines, such as interferon-gamma (IFN-γ) and tumour necrosis factor-alpha (TNF-α) and various chemokines (e.g., CCL2, CCL3 and CCL5) that assist in the control of the parasite infection. Our aim is to evaluate the effect of simvastatin on cardiac inflammation using a cardiotropic strain of T. cruzi (Colombian) in a murine model and to assess the modulation of immune parameters and epimastigote replication by statins in vitro
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