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

Abstract

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.

Plasma Xanthine Oxidase Activity Is Predictive of Cardiovascular Disease in Patients with Chronic Kidney Disease, Independently of Uric Acid Levels

“…In vitro studies are necessary to determine the potential deleterious effect of XO on the vascular wall, especially on endothelial dysfunction as it has already been described for uric acid [31. ]…”

Fructose metabolism and metabolic disease

“…Moreover, elevated serum uric acid levels and gout are associated with other cardiometabolic risk factors in diverse populations (76)(77)(78). A substantial body of work suggests that increased uric acid levels may independently regulate important aspects of metabolism and contribute to cardiometabolic risk (79)(80)(81)(82)(83). However, Mendelian randomization studies do not strongly support a causal role for circulating uric acid in mediating cardiometabolic disease (84).…”

Associations between serum uric acid concentrations and metabolic syndrome and its components in the PREDIMED study

“…SUA levels are also considered to be an independent risk factor for the incidence of type 2 diabetes (T2D) [9]. High SUA concentrations commonly precede the development of insulin resistance [10,11] in experimental studies [12]. Thus, several authors have suggested that hyperuricemia may be a new marker for metabolic syndrome (MetS) [13].…”