Analysis of the pro-inflammatory mechanisms of urate hydroperoxide in innate immunity: the participation of redox modulated proteins and the inflammassome pathway

Abstract

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. According to the Brazilian Health Ministry, CD caused 963 thousand deaths ofindividuals over 30 years old in 2009. It corresponded to approximately 20% of the population at this age group. 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 tissue 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 myeloperoxidase 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, was able to oxidize uric acid present in human plasma. The one-electron-oxidation of uric acid by myeloperoxidase in the presence of hydrogen peroxide generates uric acid free radicals, unstable intermediates and allantoin. In the presence of superoxide radical, a situation that mimics the oxidative burst by inflammatory cells, the uratehydroperoxidewas identified as aproduct that,in this context, might oxidize proteins susceptible to redox modulation. Uratehydroperoxide is a strong oxidant and can oxidize thiol groups from proteins, altering their functions.Among these proteins, the multiproteic complex of the inflammassomes shows great relevance, since once activated, it signalizes aproteoliticaction with activation of caspase-1 and post-translational modification of pro-inflammatory cytokines. Thus, the production of hydroperoxideurate ispossibly a pro-inflammatory factor responsible for the propagation of tissue damage at the vascular sheet, which might explain why the uric acid, even at soluble form, represents a risk factor to the development of cardiovascular diseases. Besides, it is possible to elucidate the redox modulation mechanisms involved at activation of inflammassome cascade, investigate the oxidation of key proteins (like the peroxiredoxins)at redox control and indentify synthesized proteins or post-translational altered ones due to the cells incubation in the presence of uratehydroperoxide.