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

TITLE=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

JOURNAL=Frontiers in Immunology

VOLUME=10

YEAR=2020

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2019.02955

DOI=10.3389/fimmu.2019.02955

ISSN=1664-3224

ABSTRACT=<p>Chagas disease is caused by <italic>Trypanosoma cruzi</italic> 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. HP<sub>24</sub>, 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 HP<sub>24</sub> in <italic>T. cruzi</italic>-infected macrophages, which have not yet been elucidated. We show for the first time that HP<sub>24</sub> increases expression of VEGF-A and eNOS through PI3K/AKT/mTOR and PPARγ pathways and that HP<sub>24</sub> inhibits iNOS expression and NO release, a pro-inflammatory mediator, through PPARγ-dependent mechanisms. Furthermore, this study shows that HP<sub>24</sub> modulates H<sub>2</sub>O<sub>2</sub> production in a PPARγ-dependent manner. It is also demonstrated that this new PPARγ ligand inhibits the NF-κB pathway. HP<sub>24</sub> 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.</p>