Treatment with Fenofibrate plus a low dose of Benznidazole attenuates cardiac dysfunction in experimental Chagas disease

Abstract

Trypanosoma cruzi induces serious cardiac alterations during the chronic infection. Intense inflammatory response observed from the beginning of infection, is critical for the control of parasite proliferation and evolution of Chagas disease. Peroxisome proliferator-activated receptors (PPAR)-α, are known to modulate inflammation.In this study we investigated whether a PPAR-α agonist, Fenofibrate, improves cardiac function and inflammatory parameters in a murine model of T. cruzi infection. BALB/c mice were sequentially infected with two T. cruzi strains of different genetic background. Benznidazole, commonly used as trypanocidal drug, cleared parasites but did not preclude cardiac pathology, resembling what is found in human chronic chagasic cardiomyopathy. Fenofibrate treatment restored to normal values the ejection and shortening fractions, left ventricular end-diastolic, left ventricular end-systolic diameter, and isovolumic relaxation time. Moreover, it reduced cardiac inflammation and fibrosis, decreased the expression of pro-inflammatory (IL-6, TNF-α and NOS2) and heart remodeling mediators (MMP-9 and CTGF), and reduced serum creatine kinase activity. The fact that Fenofibrate partially inhibited NOS2 expression and NO release in the presence of a PPAR-α non-competitive inhibitor, suggested it also acted through PPAR-α-independent pathways. Since IκBα cytosolic degradation was inhibited by Fenofibrate, it can be concluded that the NFκB pathway has a role in its effects. Thus, we demonstrate that Fenofibrate acts through PPAR-α-dependent and -independent pathways.Our study shows that combined treatment with Fenofibrate plus Benznidazole is able both to reverse the cardiac dysfunction associated with the ongoing inflammatory response and fibrosis and to attain parasite clearance in an experimental model of Chagas disease.

Pyridinecarboxylic Acid Derivative Stimulates Pro-Angiogenic Mediators by PI3K/AKT/mTOR and Inhibits Reactive Nitrogen and Oxygen Species and NF-κB Activation Through a PPARγ-Dependent Pathway in T. cruzi-Infected Macrophages

“…This is in agreement with previous results from our group using HP 24 using an in vivo model of acute infection (19). Also, we showed similar results using a PPARα ligand, in an in vivo model of chronic infection (29). Besides, Rodrigues et al show reduction of skeletal muscle parasitism (36).…”

“…Several authors have shown that different PPARγ ligands exert anti-inflammatory effects through the inhibition of NF-κB-dependent inflammatory genes (60)(61)(62)(63). In the same line of evidence, we demonstrated the anti-inflammatory properties of several PPAR ligands in different models of T. cruzi infection (15,16,29). Herein, we evidenced that HP 24 inhibits NF-κB activation in T. cruzi-infected macrophages.…”

“…We have previously shown that different PPAR ligands are potent inhibitors of inflammatory mediators like NO, IL-1β, IL-6, and TNFα, through PPAR-dependent and -independent pathways in T. cruzi-infected macrophages and cardiomyocytes (15,16,26,29). In the present study, we determined the antiinflammatory efficacy of HP 24 .…”

“…It has been widely demonstrated that NF-κB is involved in the pro-inflammatory response in different models of T. cruzi infection (15,29,31,57,58). This transcriptional factor regulates the expression of several pro-inflammatory cytokines and chemokines such as TNFα, IL-1β, IL-6, and FIGURE 9 | Schematic representation of the pro-angiogenic and anti-inflammatory actions of HP 24 in T. cruzi-infected macrophages.…”

“…Total and cytosolic protein extracts were prepared as described previously by our group (19,29). Protein concentration was determined by the Bradford method using a commercial protein assay (Bio-Rad, USA) and bovine serum albumin (BSA, Sigma-Aldrich Co, USA) as a standard (30).…”