Unraveling the effects of uric acid on endothelial cells: A global proteomic study

• Published in: Redox biology Vol. 82; p. 103625
• Main Authors: Dempsey, Bianca, Pereira da Silva, Beatriz, Cruz, Litiele Cezar, Vileigas, Danielle, Silva, Amanda R.M., Pereira da Silva, Railmara, Meotti, Flavia Carla
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.05.2025; Elsevier
• Subjects: Cell Adhesion - drug effects; Cell Movement - drug effects; Endothelial cell damage; Endothelial Cells - drug effects; Endothelial Cells - metabolism; Human Umbilical Vein Endothelial Cells - drug effects; Human Umbilical Vein Endothelial Cells - metabolism; Humans; HUVEC; Inflammation; Oxidation-Reduction; Oxidative Stress - drug effects; Proteome - metabolism; Proteomics; Proteomics - methods; PXDN; Research Paper; Uric acid; Uric Acid - metabolism; Uric Acid - pharmacology; HUVEC; Endothelial cell damage; Inflammation; Uric acid; Proteomics; PXDN
• ISSN: 2213-2317; 2213-2317
• DOI: 10.1016/j.redox.2025.103625

This work aims to understand how normouricemic levels of uric acid can induce endothelial dysfunction seeking global proteomic alterations in Human Umbilical Vein cells (HUVEC). It reveals significant alterations in redox-sensitive and antioxidant proteins, chaperones, and proteins associated with cell migration and adhesion in response to uric acid exposure. Monitoring cellular oxidation with the roGFP2-Grx1 probe proved increased oxidation levels induced by uric acid, which can be attenuated by peroxidasin (PXDN) inhibition, suggesting a regulatory role for PXDN in mitigating oxidative stress induced by uric acid. As a consequence of uric acid oxidation and the formation of reactive intermediate, we identified adducts in proteins (+140 kDa) in a novel post-translation modification named uratylation. Increased misfolded protein levels and p62 aggregation were also found, indicating disturbances in cellular proteostasis. Furthermore, uric acid promoted monocyte adhesion and upregulated ICAM and VCAM protein levels, implicating a pro-inflammatory response in endothelial cells. These findings provide critical insights into the molecular mechanisms underlying vascular damage associated with uric acid. [Display omitted] •First proteomics study revealing the modulation of protein abundance in HUVEC upon physiological concentrations of uric acid.•Chaperones, redox signaling proteins, proteins related to protein degradation and to the inflammatory processes were changed.•Uric acid induced an increase in oxidation levels in cells.•PXDN inhibition or silencing decreased urate-dependent oxidation.•Uric acid increased protein misfolding and monocyte adhesion.