Anti‐Inflammatory Effects of Quercetin on High‐Glucose and Pro‐Inflammatory Cytokine Challenged Vascular Endothelial Cell Metabolism

SCOPE: Pro‐inflammatory stimuli such as hyperglycemia and cytokines have been shown to negatively affect endothelial cell functions. The aim of this study is to assess the potential of quercetin and its human metabolites to overcome the deleterious effects of hyperglycemic or inflammatory conditions on the vascular endothelium by modulating endothelial cell metabolism. METHODS AND RESULTS: A metabolomics approach enabled identification and quantification of 27 human umbilical vein endothelial cell (HUVEC) metabolites. Treatment of HUVECs with high‐glucose concentrations causes significant increases in lactate and glutamate concentrations. Quercetin inhibits glucose‐induced increases in lactate and adenosine 5′‐triphosphate (ATP) and also increased inosine concentrations. Tumor necrosis factor α‐treatment (TNFα) of HUVECs causes increases in asparagine and decreases in aspartate concentrations. Co‐treatment with quercetin reduces pyruvate concentrations compared to TNFα‐only treated controls. Subsequently, it was shown that quercetin and its HUVEC phase‐2 conjugates inhibit adenosine deaminase, xanthine oxidase and 5′nucleotidase (CD73) but not ectonucleoside triphosphate diphosphohydrolase‐1 (CD39) or purine nucleoside phosphorylase activities. CONCLUSION: Quercetin was shown to alter the balance of HUVEC metabolites towards a less inflamed phenotype, both alone and in the presence of pro‐inflammatory stimuli. These changes are consistent with the inhibition of particular enzymes involved in purine metabolism by quercetin and its HUVEC metabolites.