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

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)