Uric acid induces radical oxygen species formation, endothelial inflammation, and endothelial dysfunction which contributes to the progression of atherosclerosis. Febuxostat and allopurinol differentially alter uric acid transporter function in human embryonic kidney cells. We hypothesized that endothelial cells express uric acid transporters that regulate intracellular uric acid concentration and that modulation of these transporters by febuxostat and allopurinol contributes to their different impact on cardiovascular mortality. Gene expression of uric acid transporters was determined in isolated human umbilical vein endothelial cells (HUVEC) and in human aortic endothelial cells (HAEC). Cultured HUVEC were studied for the effect of allopurinol and febuxostat on intracellular uric acid concentrations, gene expression of uric acid transporters, and cell count after exposure to uric acid in medium. Data is reported as median (range). HUVEC and HAEC expressed glucose transporter 9 (GLUT9), multidrug resistance protein 4 (MRP4), breast cancer resistance protein (BRCP), and sodium-dependent dicarboxylate transporter (NaDC3) at mRNA level. Allopurinol did not affect intracellular uric acid concentrations. In contrast, febuxostat 10µM and 20µM increased intracellular uric acid concentration by 32% (0-42%) and 75 (21-111%) during exposure to 100µM uric acid; and by 62% (23-98%) and 88% (58-150%) during exposure to 350µM uric acid. Allopurinol did not alter mRNA expression of uric acid transporters. In contrast, febuxostat increased mRNA expression of GLUT9, reduced that of MRP4, and did not affect BCRP. These findings could explain the higher cardiovascular mortality for febuxostat as compared to allopurinol in patients with gout.

Date Submitted: 2022-12-06