Oxidation of uric acid by the endothelial peroxidase peroxidasin: investigation of the mechanisms of vascular disfunction induced by uric acid

Abstract

Peroxidasin (PXDN) is a heme-peroxidase expressed mainly at the extracellular matrix of the vascular endothelium. This enzyme catalyzes the oxidation of chloride or bromide by hydrogen peroxide producing the respective hypohalous acid. The products of PXDN oxidize collagen residues forming cross-linked chains at the basement membrane. In spite of this evidence, the physiological function of PXDN is not fully understood. A potential substrate for PXDN is uric acid. Uric acid is the end product of purine metabolism and accumulates in human plasma. It is oxidized by mieloperoxidase and lactoperoxidase to generate urate free radical and urate hydroperoxide. These oxidizing agents are associated to endothelial dysfunction and atherogenesis. The oxidation of uric acid by PXDN in the vascular system could be harmful either by the formation of urate free radical and urate hydroperoxide or by deviating PXDN of its original function. Therefore, the first aim of this project is to investigate whether PXDN oxidizes uric acid and if this oxidation is likely to occur in plasma. Next, it will be to investigate the products of this oxidation. Previous data from our group revealed that uric acid reacted with a peroxidase released from endothelial cells (HUVECs). Therefore, the third aim of this project will be to investigate if the peroxidase released from HUVECs is PXDN and if the products of uric acid in this condition are the same of those produced by the recombinant protein. The fourth aim of this study is to evaluate if uric acid affects the formation of sulfimine cross-link in collagen IV by PXDN. In summary, the development of this project aims to understand the basic mechanisms responsible, at least in part, by endothelial dysfunction and vascular homeostasis disruption. By developing this project it is expected to better understand pathological processes as occurs in Atherosclerosis within a therapeutic perspective. (AU)