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.

Federico Nicolás Penas,María Jimena Rada,Azul Victoria Pieralisi,María Grazia Ferlin,Davide Carta,Gerardo A Mirkin,María Elena Sales,Ágata Carolina Cevey,Nora Beatriz Goren

doi:10.3389/fimmu.2019.02955

Abstract

Chagas disease is caused by Trypanosoma cruzi infection and represents an important public health concern in Latin America. Macrophages are one of the main infiltrating leukocytes in response to infection. Parasite persistence could trigger a sustained activation of these cells, contributing to the damage observed in this pathology, particularly in the heart. HP24, a pyridinecarboxylic acid derivative, is a new PPARγ ligand that exerts anti-inflammatory and pro-angiogenic effects. The aim of this work was to deepen the study of the mechanisms involved in the pro-angiogenic and anti-inflammatory effects of HP24 in T. cruzi-infected macrophages, which have not yet been elucidated. We show for the first time that HP24 increases expression of VEGF-A and eNOS through PI3K/AKT/mTOR and PPARγ pathways and that HP24 inhibits iNOS expression and NO release, a pro-inflammatory mediator, through PPARγ-dependent mechanisms. Furthermore, this study shows that HP24 modulates H2O2 production in a PPARγ-dependent manner. It is also demonstrated that this new PPARγ ligand inhibits the NF-κB pathway. HP24 inhibits IKK phosphorylation and IκB-α degradation, as well as p65 translocation to the nucleus in a PPARγ-dependent manner. In Chagas disease, both the sustained increment in pro-inflammatory mediators and microvascular abnormalities are crucial aspects for the generation of cardiac damage. Elucidating the mechanism of action of new PPARγ ligands is highly attractive, given the fact that it can be used as an adjuvant therapy, particularly in the case of Chagas disease in which inflammation and tissue remodeling play an important role in the pathophysiology of this disease.

Highlights

Trypanosoma cruzi (T. cruzi) is a protozoan parasite that causes Chagas disease, the main cause of infectious dilated cardiomyopathy all over the world [1]
To test whether signaling of HP24 through PPARγ correlates with changes in cell parasitism, we performed silencing assays to knock down PPARγ
The silencing effectiveness of PPARγ siRNA 7863 and 7864 was verified in peritoneal macrophages infected in vitro with T. cruzi (Figure 1A), as well as in Transfected or non-transfected cells were treated with HP24 (100 μM) for 48 h

Summary

Introduction

Trypanosoma cruzi (T. cruzi) is a protozoan parasite that causes Chagas disease, the main cause of infectious dilated cardiomyopathy all over the world [1]. This vector-borne disease affects millions of people in South America and, in recent years, it has been regarded as a risk factor for transfusion and vertical transmission in countries without vector-borne disease transmission control. Inflammation is involved in protection but parasite persistence leads to chronic inflammation. This impairs adequate repair leading to cumulative damage that may cause death due to cardiac insufficiency [2]. The mechanisms underlying progression to CCC have not been fully understood, it is generally accepted that inflammation persistence plays a predominant role [4]

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