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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‐dependent 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 endothelial dysfunction. Uric acid inhibited insulin‐induced endothelial nitric oxide synthase (eNOS) phosphorylation and NO production more substantially than endothelin‐1 expression in HUVECs, with IC50 of 51.0, 73.6, and 184.2, respectively. Suppression of eNOS phosphorylation 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 hyperuricemic 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 allopurinol 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.—Choi, Y.‐J., Yoon, Y., Lee, K.‐Y., Hien, T. T., Kang, K. W., Kim, K.‐C., Lee, J., Lee, M.‐Y., Lee, S. M., Kang, D.‐H., Lee, B.‐H. Uric acid induces endothelial dysfunction by vascular insulin resistance associated with the impairment of nitric oxide synthesis. FASEB J. 28, 3197–3204 (2014). www.fasebj.org