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Effect of the urate hydroperoxide on the activation of protein disulfide isomerase and NADPH oxidase (PDI-Nox) in inflammatory processes and cardiovascular disease

Grant number: 11/15297-3
Support Opportunities:Scholarships in Brazil - Master
Effective date (Start): March 01, 2012
Effective date (End): February 28, 2014
Field of knowledge:Biological Sciences - Biochemistry - Metabolism and Bioenergetics
Principal Investigator:Flavia Carla Meotti
Grantee:Eliziane de Souza Patricio
Host Institution: Instituto de Química (IQ). Universidade de São Paulo (USP). São Paulo , SP, Brazil


The cardiovascular disease (CD) related to the formation of atheroma plaques is the main cause of myocardial infarction and death in Brazil and developed countries. The CDs are often related to metabolic syndromes mainly hyperlipidemia and hyperuricemia. It has been well accepted that atherogenesis is accompanied of an inflammatory process in the vascular tisue in response to structural changes in lipoproteins due to the oxidation of lipids. In accordance to this evidence, the levels and the activity of the pro-oxidant enzyme myeloperoxidase are associated to the progression of atherogenesis. The myeloeproxidase is present in large amounts in neutrophils and can also be expressed in macrophages. It was recently demonstrated that myeloperoxidase, either purified or in activated neutrophils were able to oxidize uric acid present in human plasma. The one electron oxidation of uric acic by myeloperoxidase in the presence of hydrogen peroxide generates uric acid free radicals, unstable intermediates and allanthoin. In the presence of superoxide radical, a situation that mimics the oxidative burst by inflammatory cells it was identified the urate hydroperoxide product. Urate hydroperoxide is a strong oxidant and can oxidize thiol groups from proteins, altering their functions. In this context, the cysteines from the protein disulfide isomerase (PDI) from vascular tissue are potential targets to the oxidation by the urate hydroperoxide. The oxidation of PDI signalizes activation of NADPH oxidase (Nox) in vascular smooth muscle cells (VSMC) and in neutrophils. This triggers the formation of superoxide, leading to the progression of the inflammation, decreasing the bioavailability of nitric oxide and consequently diminishing vasorrelaxation. Taking this into account, the activation of PDI-Nox pathway in vascular cells by the urate hydroperoxide might explain, at least in part, the mechanisms by which plasma uric acid is a risk factor to the development of CD in humans.

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Scientific publications
(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)
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, . (11/15297-3, 11/18106-4, 13/07937-8, 13/02195-3)
Academic Publications
(References retrieved automatically from State of São Paulo Research Institutions)
PATRICIO, Eliziane de Souza. Evaluation of the interaction of urate hydroperoxide with protein disulfide isomerase (PDI) in inflammatory processes. 2014. Master's Dissertation - Universidade de São Paulo (USP). Conjunto das Químicas (IQ e FCF) (CQ/DBDCQ) São Paulo.

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