Uric Acid Reacts with Peroxidasin, Decreases Collagen IV Crosslink, Impairs Human Endothelial Cell Migration and Adhesion

Uric acid is considered the main substrate for peroxidases in plasma. The oxidation of uric acid by human peroxidases generates urate free radical and urate hydroperoxide, which might affect endothelial function and explain, at least in part, the harmful effects of uric acid on the vascular system....

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Published inAntioxidants Vol. 11; no. 6; p. 1117
Main Authors Dempsey, Bianca, Cruz, Litiele Cezar, Mineiro, Marcela Franco, da Silva, Railmara Pereira, Meotti, Flavia Carla
Format Journal Article
LanguageEnglish
Published Basel MDPI AG 04.06.2022
MDPI
Subjects
Antibodies
Cardiovascular diseases
Cell migration
Collagen
Collagen (type IV)
collagen IV
Cross-linking
Endothelial cells
Enzymes
Experiments
Extracellular matrix
Fibrosis
Free radicals
Heme
HUVEC
Oxidation
Oxidative stress
Peroxidase
peroxidasin
Plasma
Plasmids
Reagents
Secretome
Uric acid
Vascular system
Brazil
United States > US
Germany
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Summary:Uric acid is considered the main substrate for peroxidases in plasma. The oxidation of uric acid by human peroxidases generates urate free radical and urate hydroperoxide, which might affect endothelial function and explain, at least in part, the harmful effects of uric acid on the vascular system. Peroxidasin (PXDN), the most recent heme-peroxidase described in humans, catalyzes the formation of hypobromous acid, which mediates collagen IV crosslinks in the extracellular matrix. This enzyme has gained increasing scientific interest since it is associated with cardiovascular disease, cancer, and renal fibrosis. The main objective here was to investigate whether uric acid would react with PXDN and compromise the function of the enzyme in human endothelial cells. Urate decreased Amplex Red oxidation and brominating activity in the extracellular matrix (ECM) from HEK293/PXDN overexpressing cells and in the secretome of HUVECs. Parallelly, urate was oxidized to 5-hydroxyisourate. It also decreased collagen IV crosslink in isolated ECM from PFHR9 cells. Urate, the PXDN inhibitor phloroglucinol, and the PXDN knockdown impaired migration and adhesion of HUVECs. These results demonstrated that uric acid can affect extracellular matrix formation by competing for PXDN. The oxidation of uric acid by PXDN is likely a relevant mechanism in the endothelial dysfunction related to this metabolite.
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These authors contributed equally to this work.
ISSN:2076-3921
2076-3921
DOI:10.3390/antiox11061117