Oxidation of uric acid by myeloperoxidase in inflammatory processes and the implications for cardiovascular disease

• Grant number: 11/18106-4
• Support Opportunities: Research Grants - Young Investigators Grants
• Duration: March 01, 2012 - February 28, 2017
• Field of knowledge: Biological Sciences - Biochemistry
• 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 grant(s): 18/14898-2 - Investigations of the redox processes in inflammatory response and associated pathologies, AP.JP2
• Associated scholarship(s): 15/21563-9 - Study of the paper uric acid and redox modulation on the system cell innate immune microbicide activity, BP.DD; 14/20216-0 - Effect of urate hydroperoxide on the protein disulfide isomerase and tioredoxin protein interaction in inflammatory conditions, BP.IC; 14/10161-4 - Study of the relationship between the level of plasma antioxidants and carotid intima-media thickness in a longitudinal study on Adult Health (ELSA-Brazil), BP.PD; + associated scholarships 14/01936-2 - The role of uric acid and its metabolites on the microbicidal activity of innate immune cells, BP.IC; 13/23099-2 - Investigation on the redox modulation of inflammassome pathway: the pro-inflammatory effect of urate hydroperoxide, BP.IC; 13/02195-3 - Analysis of the pro-inflammatory mechanisms of urate hydroperoxide in innate immunity: the participation of redox modulated proteins and the inflammassome pathway, BP.DR - associated scholarships

Abstract

Cardiovascular disease (CD) due to atherosclerosis is the main cause of death in Brazil and developed countries. The atherogenesis is often associated with an impairment of the metabolism like hyperlipidemia and hyperuricemia. Overall, atherogenesis is accompanied of inflammatory process in the vase. In this situation, the level and the activity of myeloperoxidase, a pro-inflammatory enzyme from neutrophils and macrophage are strictly associated to the progression of atheroma. Myeloperoxidase oxidizes chloride and produces chlorine bleach to counteract infection. The enzyme also oxidizes other endogenous substrates and its products convert low density lipoprotein (LDL) to a high uptake form that promotes formation of foam cells, impair reverse cholesterol transport, destabilize atherosclerotic plaque and promote endothelial dysfunction. Recently, we demonstrated that myeloperoxidase oxidizes uric acid yielding free radicals, unstable intermediates and allantoin. Our interest in the oxidation of uric acid by myeloperoxidase has been raised because of the strong correlation between hyperuricemia and CD. In the presence of superoxide, as occurs during the inflammatory oxidative burst, we identified the formation of urate hydroperoxide, a strong oxidant compound. Because it is highly oxidant, urate hydroperoxide can oxidize thiol from proteins in inflammatory cascades and it might exacerbate inflammation and vascular tissue injury. In this context, the aim of the present project consists to investigate the effect of urate hydroperoxide on signaling inflammatory proteins that are sensitive to redox modulation. The pathways that will be investigated include the inflammassome proteins and the nicotinamide adenine dinucleotide oxidase (NADPH oxidase) dependent on the protein disulfide isomerase (PDI). In addition, the reaction of urate hydroperoxide with peroxide detoxifying proteins, the peroxiredorexins, also will be investigated. Another aim of the present project is to standardize a sensitive technique for detection of urate hydroperoxide produced by inflammatory cells in plasma. The detection of urate hydroperoxide that is being formed in vascular inflammation may emerge as a biomarker to predict CD and myocardial infarction. (AU)

Scientific publications

(6)

(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)

M.S. SANTANA; K.P. NASCIMENTO; P.A. LOTUFO; I.M. BENSEÑOR; F.C. MEOTTI. Allantoin as an independent marker associated with carotid intima-media thickness in subclinical atherosclerosis. Brazilian Journal of Medical and Biological Research, v. 51, n. 8, 2018-06-18. (11/18106-4, 13/07937-8)

MINEIRO, MARCELA FRANCO; PATRICIO, ELIZIANE DE SOUZA; PEIXOTO, ALBERT SOUZA; SILVA ARAUJO, THAIS LARISSA; DA SILVA, RAILMARA PEREIRA; SOARES MORETTI, ANA IOCHABEL; LIMA, FILIPE SILVA; MARTINS LAURINDO, FRANCISCO RAFAEL; MEOTTI, FLAVIA CARLA. Urate hydroperoxide oxidizes endothelial cell surface protein disulfide isomerase-A1 and impairs adherence. BIOCHIMICA ET BIOPHYSICA ACTA-GENERAL SUBJECTS, v. 1864, n. 3, MAR 2020. (11/18106-4, 13/07937-8)

CARVALHO, LARISSA A. C.; LOPES, JOAO P. P. B.; KAIHAMI, GILBERTO H.; SILVA, RAILMARA P.; BRUNI-CARDOSO, ALEXANDRE; BALDINI, REGINA L.; MEOTTI, FLAVIA C.. Uric acid disrupts hypochlorous acid production and the bactericidal activity of HL-60 cells. REDOX BIOLOGY, v. 16, p. 179-188, JUN 2018. (11/18106-4, 13/07937-8)

SILVA, RAILMARA P.; CARVALHO, LARISSA A. C.; PATRICIO, ELIZIANE S.; BONIFACIO, JOAO P. P.; CHAVES-FILHO, ADRIANO B.; MIYAMOTO, SAYURI; MEOTTI, FLAVIA C.. Identification of urate hydroperoxide in neutrophils: A novel pro-oxidant generated in inflammatory conditions. Free Radical Biology and Medicine, v. 126, p. 177-186, OCT 2018. (13/07937-8, 11/18106-4)

PATRICIO, ELIZIANE S.; PRADO, FERNANDA M.; DA SILVA, RAILMARA P.; CARVALHO, LARISSA A. C.; PRATES, MARCUS V. C.; DADAMOS, TONY; BERTOTTI, MAURO; DI MASCIO, PAOLO; KETTLE, ANTHONY J.; MEOTTI, FLAVIA C.. Chemical Characterization of Urate Hydroperoxide, A Pro-oxidant Intermediate Generated by Urate Oxidation in Inflammatory and Photoinduced Processes. Chemical Research in Toxicology, v. 28, n. 8, p. 1556-1566, AUG 2015. (11/15297-3, 11/18106-4, 13/07937-8, 13/02195-3)

CARVALHO, LARISSA A. C.; TRUZZI, DANIELA R.; FALLANI, THAMIRIS S.; ALVES, SIMONE V.; TOLEDO, JOSE CARLOS; AUGUSTO, OHARA; NETTO, LUIS E. S.; MEOTTI, FLAVIA C.. Urate hydroperoxide oxidizes human peroxiredoxin 1 and peroxiredoxin 2. Journal of Biological Chemistry, v. 292, n. 21, p. 8705-8715, MAY 26 2017. (11/18106-4, 13/07937-8)