Effect of urate hydroperoxide on the oxidation extracellular surface thiol-proteins in endothelial cells and the relation with cellular spreading, adhesion and proliferation

• Grant number: 20/01394-6
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• Effective date (Start): August 01, 2020
• Effective date (End): July 31, 2024
• Field of knowledge: Biological Sciences - Biochemistry - Metabolism and Bioenergetics
• Principal Investigator: Flavia Carla Meotti
• Grantee: Danielle Fernandes Vileigas
• Host Institution: Instituto de Química (IQ). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Associated research grant: 18/14898-2 - Investigations of the redox processes in inflammatory response and associated pathologies, AP.JP2

Abstract

We have demonstrated that the oxidation of uric acid occurs at the early events of Atherosclerosis and could be associated to vascular damage and progression of the disease. Oxidation of uric acid by peroxidases generates urate free radical and urate hydroperoxide. Urate hydroperoxide efficiently oxidizes the recombinant thiol-protein PDI (Protein Disulfide Isomerase), an important protein involved in vascular remodeling, platelet activation, aggregation, thrombosis and integrin signaling. We also demonstrated that urate hydroperoxide oxidizes PDI at the extracellular surface of endothelial (HUVEC) cells. It is possible that urate hydroperoxide oxidizes other cell surface thiol-proteins either directly or indirectly through protein disulfide exchange and this might be also involved in vascular remodeling. To identify which proteins are being oxidizing and interfering in the cellular adhesion to the extracellular matrix, a global study of extracellular cell surface redox proteomics need to be performed. The redox alterations on endothelial cell surface proteins will be correlated with morphological and functional activities of the cell, including cell spreading, adhesion and migration. Specific proteins involved in these processes will be identified by fluorescence microscopy. These analyses will elucidate the role of thiol-protein redox modification in the interaction with extracellular matrix and with vascular remodeling. This is highly relevant in the field, since we still don't know how much physiological oxidants can interfere in these cellular process. (AU)