Abstract
Urate and myeloperoxidase (MPO) are associated with adverse outcomes in cardiovascular disease. In this study, we assessed whether urate is a likely physiological substrate for MPO and if the products of their interaction have the potential to exacerbate inflammation. Urate was readily oxidized by MPO and hydrogen peroxide to 5-hydroxyisourate, which decayed to predominantly allantoin. The redox intermediates of MPO were reduced by urate with rate constants of 4.6 × 10(5) M(-1) s(-1) for compound I and 1.7 × 10(4) M(-1) s(-1) for compound II. Urate competed with chloride for oxidation by MPO and at hyperuricemic levels is expected to be a substantive substrate for the enzyme. Oxidation of urate promoted super-stoichiometric consumption of glutathione, which indicates that it is converted to a free radical intermediate. In combination with superoxide and hydrogen peroxide, MPO oxidized urate to a reactive hydroperoxide. This would form by addition of superoxide to the urate radical. Urate also enhanced MPO-dependent consumption of nitric oxide. In human plasma, stimulated neutrophils produced allantoin in a reaction dependent on the NADPH oxidase, MPO and superoxide. We propose that urate is a physiological substrate for MPO that is oxidized to the urate radical. The reactions of this radical with superoxide and nitric oxide provide a plausible link between urate and MPO in cardiovascular disease.
Highlights
Uric acid (7,9-dihydro-1H-purine-2,6,8(3H)-trione) is the end product of purine nucleotide metabolism and is mostly present in the human plasma as the urate mono-anion [1]
MPO is the most abundant enzyme in neutrophils and is proposed to play a central role in host defense [20]. It catalyzes the production of hypochlorous acid from hydrogen peroxide and chloride [21] and acts as a classical peroxidase [22]
Materials—Uric acid, glutathione (GSH), bovine liver catalase, 3,3Ј,5,5Ј-tetramethylbenzidine, methionine, N-ethylmaleimide, phorbol 12-myristate 13-acetate (PMA), superoxide dismutase, tyrosine, sodium azide, and diphenyliodonium were purchased from Sigma
Summary
In combination with superoxide and hydrogen peroxide, MPO oxidized urate to a reactive hydroperoxide This would form by addition of superoxide to the urate radical. We propose that urate is a physiological substrate for MPO that is oxidized to the urate radical. It is believed to act as a danger signal that regulates inflammation [13] These pro-oxidant and pro-inflammatory effects of urate could explain the association existing between hyperuricemia and the risk for cardiovascular disease and hypertension (14 –18). MPO is the most abundant enzyme in neutrophils and is proposed to play a central role in host defense [20] It catalyzes the production of hypochlorous acid from hydrogen peroxide and chloride [21] and acts as a classical peroxidase (see Scheme 1) [22].
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
