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
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...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2020-01-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/article/10.3389/fimmu.2019.02955/full |
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| author | Federico Nicolás Penas Federico Nicolás Penas Davide Carta Ágata Carolina Cevey Ágata Carolina Cevey María Jimena Rada María Jimena Rada Azul Victoria Pieralisi Azul Victoria Pieralisi María Grazia Ferlin María Elena Sales Gerardo A. Mirkin Gerardo A. Mirkin Nora Beatriz Goren Nora Beatriz Goren |
| author_facet | Federico Nicolás Penas Federico Nicolás Penas Davide Carta Ágata Carolina Cevey Ágata Carolina Cevey María Jimena Rada María Jimena Rada Azul Victoria Pieralisi Azul Victoria Pieralisi María Grazia Ferlin María Elena Sales Gerardo A. Mirkin Gerardo A. Mirkin Nora Beatriz Goren Nora Beatriz Goren |
| author_sort | Federico Nicolás Penas |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-10T09:18:02Z |
| format | Article |
| id | doaj.art-c762bd450ddd4e6991ccea302c57b243 |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-12-10T09:18:02Z |
| publishDate | 2020-01-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-c762bd450ddd4e6991ccea302c57b2432022-12-22T01:54:47ZengFrontiers Media S.A.Frontiers in Immunology1664-32242020-01-011010.3389/fimmu.2019.02955490529Pyridinecarboxylic 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 MacrophagesFederico Nicolás Penas0Federico Nicolás Penas1Davide Carta2Ágata Carolina Cevey3Ágata Carolina Cevey4María Jimena Rada5María Jimena Rada6Azul Victoria Pieralisi7Azul Victoria Pieralisi8María Grazia Ferlin9María Elena Sales10Gerardo A. Mirkin11Gerardo A. Mirkin12Nora Beatriz Goren13Nora Beatriz Goren14Departamento de Microbiología, Parasitología e Inmunología, Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires, ArgentinaInstituto de Investigaciones Biomédicas en Retrovirus y Sida (INBIRS), CONICET-Universidad de Buenos Aires, Buenos Aires, ArgentinaDepartment of Pharmaceutical and Pharmacological Sciences, University of Padova, Padova, ItalyDepartamento de Microbiología, Parasitología e Inmunología, Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires, ArgentinaInstituto de Investigaciones Biomédicas en Retrovirus y Sida (INBIRS), CONICET-Universidad de Buenos Aires, Buenos Aires, ArgentinaDepartamento de Microbiología, Parasitología e Inmunología, Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires, ArgentinaInstituto de Investigaciones Biomédicas en Retrovirus y Sida (INBIRS), CONICET-Universidad de Buenos Aires, Buenos Aires, ArgentinaDepartamento de Microbiología, Parasitología e Inmunología, Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires, ArgentinaInstituto de Investigaciones Biomédicas en Retrovirus y Sida (INBIRS), CONICET-Universidad de Buenos Aires, Buenos Aires, ArgentinaDepartment of Pharmaceutical and Pharmacological Sciences, University of Padova, Padova, ItalyCentro de Estudios Farmacológicos y Botánicos (CEFyBO), CONICET-Universidad de Buenos Aires, Buenos Aires, ArgentinaDepartamento de Microbiología, Parasitología e Inmunología, Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires, ArgentinaInstituto de Investigaciones en Microbiología y Parasitología Médica (IMPaM), CONICET-Universidad de Buenos Aires, Buenos Aires, ArgentinaDepartamento de Microbiología, Parasitología e Inmunología, Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires, ArgentinaInstituto de Investigaciones Biomédicas en Retrovirus y Sida (INBIRS), CONICET-Universidad de Buenos Aires, Buenos Aires, ArgentinaChagas 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.https://www.frontiersin.org/article/10.3389/fimmu.2019.02955/fullnew PPARγ ligandPI3K/AKT/mTORNF-κB pathwayTrypanosoma cruzimacrophages |
| spellingShingle | Federico Nicolás Penas Federico Nicolás Penas Davide Carta Ágata Carolina Cevey Ágata Carolina Cevey María Jimena Rada María Jimena Rada Azul Victoria Pieralisi Azul Victoria Pieralisi María Grazia Ferlin María Elena Sales Gerardo A. Mirkin Gerardo A. Mirkin Nora Beatriz Goren Nora Beatriz Goren 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 Frontiers in Immunology new PPARγ ligand PI3K/AKT/mTOR NF-κB pathway Trypanosoma cruzi macrophages |
| 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 |
| title_full | 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 |
| title_fullStr | 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 |
| title_full_unstemmed | 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 |
| title_short | 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 |
| title_sort | 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 |
| topic | new PPARγ ligand PI3K/AKT/mTOR NF-κB pathway Trypanosoma cruzi macrophages |
| url | https://www.frontiersin.org/article/10.3389/fimmu.2019.02955/full |
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