Investigations of the redox processes in inflammatory response and associated pathologies

• Grant number: 18/14898-2
• Support Opportunities: Research Grants - Young Investigators Grants - Phase 2
• Duration: May 01, 2019 - April 30, 2024
• Field of knowledge: Biological Sciences - Biochemistry - Metabolism and Bioenergetics
• Principal Investigator: Flavia Carla Meotti
• Grantee: Flavia Carla Meotti
• Host Institution: Instituto de Química (IQ). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Associated research grant: 11/18106-4 - Oxidation of uric acid by myeloperoxidase in inflammatory processes and the implications for cardiovascular disease, AP.JP
• Associated scholarship(s): 22/06870-6 - Oxidation of uric acid and association with Sepsis, BP.IC; 21/00349-0 - The genetically encoded biosensor (PxIII-roGFP) as a tool to monitor the production and role of organic peroxides in redox signaling in mammalian inflammatory cells, BP.PD; 20/12969-0 - Correlation between the oxidation of uric acid and Sepsis, BP.PD; + associated scholarships 20/01394-6 - Effect of urate hydroperoxide on the oxidation extracellular surface thiol-proteins in endothelial cells and the relation with cellular spreading, adhesion and proliferation, BP.PD; 19/16224-1 - Proteomic analysis of endothelial cells secretome: study about uric acid and Atherosclerosis development, BP.DD; 19/26473-9 - The role of urate hydroperoxide in macrophage polarization, BP.DD - associated scholarships

Abstract

During the JP-1 project we demonstrated that the oxidation of uric acid by neutrophil-peroxidases and production of urate hydroperoxide is an important event during the inflammatory oxidative burst. Urate hydroperoxide preferentially oxidized peroxiredoxins and the extracellular cell surface protein disulfide isomerase (PDI) and might affect redox signaling, inflammation, atherosclerosis and vascular remodeling. The oxidation of uric acid was significantly correlated with carotid intima-media thickness (c-IMT) in patients with subclinical atherosclerosis and the product allantoin was purposed as an independent marker for atherosclerosis. The oxidation of uric acid by neutrophil-myeloperoxidase decreased the production of hypochlorous acid and the killing activity of these cells. The relevance of this study consists in the intense debate whether uric acid plays or not a causal role in cardiovascular disease. These debates are sustained by uncertainties on the exact mechanisms of how uric acid would cause/propagate tissue damage and, therefore, an appropriate intervention regarding uric acid levels in disease has been usually neglected. Our hypothesis is that the metabolic transformation of uric acid and production of reactive oxidant intermediates could sustain inflammation by affecting cell response and vascular homeostasis. Therefore, one of the purposes of this JP-2 project is to investigate other sources for urate oxidation and production of urate hydroperoxide in the vascular system. We will investigate how this oxidation would affect extracellular matrix formation and vascular remodeling. Because urate hydroperoxide efficiently oxidizes thiol-proteins, we will seek for the role of these proteins in vascular endothelial cell function, vascular remodeling and redox signaling related to macrophage polarization. The oxidation of uric acid decreased the killing activity of neutrophil-like cells against Pseudomonas aeruginosa. In this JP-2 project we will test the clinical relevance of this effect by investigating the correlation between uric acid, allantoin and sepsis progression in patients admitted in the intensive care unit of the Hospital das Clínicas from USP. In summary, this JP-2 project intends to strength the knowledge about redox processes in inflammatory response to better understand the mechanisms of inflammation progression/resolution. Since the production of urate hydroperoxide is relevant in the inflammatory oxidative burst, the project is focused into determine its effects in the progression of inflammation in vascular homeostasis and in infection states. We will also investigate myeloperoxidase inhibitor candidates and the redox signaling dependent on peroxiredoxins because these two events are tightly related to urate hydroperoxide formation and biological effects. (AU)

Scientific publications

(5)

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

MATOS, ISAAC DE ARAUJO; DA COSTA JUNIOR, NIVAN BEZERRA; MEOTTI, FLAVIA CARLA. Integration of an Inhibitor-like Rule and Structure-based Virtual Screening for the Discovery of Novel Myeloperoxidase Inhibitors. JOURNAL OF CHEMICAL INFORMATION AND MODELING, v. 60, n. 12, p. 6408-6418, DEC 28 2020. (13/07937-8, 18/14898-2)

ROCHA, LEONARDO SILVA; DA SILVA, BEATRIZ PEREIRA; CORREIA, THIAGO M. L.; DA SILVA, RAILMARA PEREIRA; MEIRELES, DIOGO DE ABREU; PEREIRA, RAFAEL; SOARES NETTO, LUIS EDUARDO; MEOTTI, FLAVIA CARLA; QUEIROZ, RAPHAEL FERREIRA. Peroxiredoxin AhpC1 protects Pseudomonas aeruginosa against the inflammatory oxidative burst and confers virulence. REDOX BIOLOGY, v. 46, OCT 2021. (15/21563-9, 13/07937-8, 15/10411-3, 18/14898-2, 19/26473-9)

RUSSO, LILIAN CRISTINA; TOMASIN, REBEKA; MATOS, ISAAC ARAUJO; MANUCCI, ANTONIO CARLOS; SOWA, SVEN T.; DALE, KATIE; CALDECOTT, KEITH W.; LEHTIO, LARI; SCHECHTMAN, DEBORAH; MEOTTI, FLAVIA C.; et al. The SARS-CoV-2 Nsp3 macrodomain reverses PARP9/DTX3L-dependent ADP-ribosylation induced by interferon signaling. Journal of Biological Chemistry, v. 297, n. 3, SEP 2021. (18/18007-5, 18/14898-2, 19/26767-2)

PESKIN, V, ALEXANDER; MEOTTI, FLAVIA C.; KEAN, KELSEY M.; GOBL, CHRISTOPH; PEIXOTO, ALBERT SOUZA; PACE, PAUL E.; HORNE, CHRISTOPHER R.; HEATH, SARAH G.; CROWTHER, JENNIFER M.; DOBSON, RENWICK C. J.; et al. Modifying the resolving cysteine affects the structure and hydrogen peroxide reactivity of peroxiredoxin 2. Journal of Biological Chemistry, v. 296, JAN-JUN 2021. (15/10411-3, 13/07937-8, 18/14898-2)

PESKIN, ALEXANDER V.; MEOTTI, FLAVIA C.; SOUZA, LUIZ F. DE; ANDERSON, ROBERT F.; WINTERBOURN, CHRISTINE C.; SALVADOR, ARMINDO. Intra-dimer cooperativity between the active site cysteines during the oxidation of peroxiredoxin 2. Free Radical Biology and Medicine, v. 158, p. 115-125, OCT 2020. (13/07937-8, 18/14898-2, 17/12312-8)