Uric acid induces endothelial dysfunction by vascular insulin resistance associated with the impairment of nitric oxide synthesis

Endothelial dysfunction is defined as impairment of the balance between endothelium-de-pendent vasodilation and constriction. Despite evidence of uric acid-induced endothelial dysfunction, a relationship with insulin resistance has not been clearly established. In this study, we investigated the role of vascular insulin resistance in uric acid-induced endothe-lial dysfunction. Uric acid inhibited insulin-induced endothelial nitric oxide synthase (eNOS) phosphoryla-tion and NO production more substantially than endo-thelin-1 expression in HUVECs, with IC₅₀ of 51.0, 73.6, and 184.2, respectively. Suppression of eNOS phos-phorylation and NO production by uric acid was PI3K/ Akt-dependent, as verified by the transfection with p110. Treatment of rats with the uricase inhibitor allantoxanamide induced mild hyperuricemia and increased mean arterial pressure by 25%. While hyper-uricemic rats did not show systemic insulin resistance, they showed impaired vasorelaxation induced by insulin by 56%. A compromised insulin response in terms of the Akt/eNOS pathway was observed in the aortic ring of hyperuricemic rats. Coadministration with allopuri-nol reduced serum uric acid levels and blood pressure and restored the effect of insulin on Akt-eNOS pathway and vasorelaxation. Taken together, uric acid induced endothelial dysfunction by contributing to vascular insulin resistance in terms of insulin-induced NO production, potentially leading to the development of hypertension.