Effect of urate hydroperoxide on the protein disulfide isomerase and tioredoxin protein interaction in inflammatory conditions

• Grant number: 14/20216-0
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• Effective date (Start): January 01, 2015
• Effective date (End): November 30, 2015
• Field of knowledge: Biological Sciences - Biochemistry - Metabolism and Bioenergetics
• Principal Investigator: Flavia Carla Meotti
• Grantee: Thamiris Simionato Fallani
• 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

Abstract

Atherosclerosis is a preceding inflammatory process common to cardiovascular diseases (CVDs) and myeloperoxidase (MPO) is one of the major enzymes involved in this process. MPO has important role in host defense against pathogens by participating in the respiratory burst, producing hypochlorous acid from hydrogen peroxide and chloride. It has been shown that MPO can oxidize uric acid in a fast reaction (4,6x105 and 1,7x104 M-1.s-1 for enzyme compounds I and II, respectively), generating urate free radical, intermediate oxidant urate hydroperoxide and allantoin. Considering high levels of uric acid in plasma, high expression of MPO and superoxide production in atheroma plaques, one can expect that urate hydroperoxide would be produced in pathologic concentrations in vascular millieu. Urate hydroperoxide is a powerfull oxidant and protein disulfide isomerase (PDI) cysteines are potential targets of oxidation. When oxidized, PDI signals the activation of NADPH oxidase (Nox) in vascular smooth muscle cells and neutrophils, triggering the formation of superoxide and oxidative changes in cells. Besides, PDI interacts physically with thioredoxin (Trx). Although the role of this interaction is not well understood, the referred dimerization occurred in tumor B cells and is related to redox control in tumor necrosis factor receptors. This hypothesis is based on effects found in lymphocytes, but perhaps it can also be applied to cells of the innate immune response, such as neutrophils. Given the above, this project will investigate the interaction between PDI and Trx proteins during the inflammatory burst in HL-60 cells differentiated into neutrophils under the influence of the oxidant urate hydroperoxide.