title: 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.
authors.affiliation: College of Pharmacy, Research Institute of Pharmaceutical Sciences, and.
authors.forename: You-Jin
authors.initials: YJ
authors.lastname: Choi
authors.affiliation: College of Pharmacy, Research Institute of Pharmaceutical Sciences, and.
authors.forename: Yujin
authors.initials: Y
authors.lastname: Yoon
authors.affiliation: College of Pharmacy, Research Institute of Pharmaceutical Sciences, and.
authors.forename: Kang-Yo
authors.initials: KY
authors.lastname: Lee
authors.affiliation: College of Pharmacy, Research Institute of Pharmaceutical Sciences, and.
authors.forename: Tran Thi
authors.initials: TT
authors.lastname: Hien
authors.affiliation: College of Pharmacy, Research Institute of Pharmaceutical Sciences, and.
authors.forename: Keon Wook
authors.initials: KW
authors.lastname: Kang
authors.affiliation: College of Pharmacy, Research Institute of Pharmaceutical Sciences, and.
authors.forename: Kyong-Cheol
authors.initials: KC
authors.lastname: Kim
authors.affiliation: College of Pharmacy, Research Institute of Pharmaceutical Sciences, and.
authors.forename: Jeewoo
authors.initials: J
authors.lastname: Lee
authors.affiliation: College of Pharmacy, Dongguk University, Goyang, Republic of Korea;
authors.forename: Moo-Yeol
authors.initials: MY
authors.lastname: Lee
authors.affiliation: Department of Obstetrics and Gynecology, College of Medicine, Seoul National University, Seoul, Republic of Korea; Department of Obstetrics and Gynecology, Seoul Metropolitan Boramae Medical Center, Seoul, Republic of Korea; and.
authors.forename: Seung Mi
authors.initials: SM
authors.lastname: Lee
authors.affiliation: Division of Nephrology, Department of Internal Medicine, Ewha Womans University School of Medicine, Seoul, Republic of Korea.
authors.forename: Duk-Hee
authors.initials: DH
authors.lastname: Kang
authors.affiliation: College of Pharmacy, Research Institute of Pharmaceutical Sciences, and lee@snu.ac.kr.
authors.forename: Byung-Hoon
authors.initials: BH
authors.lastname: Lee
mesh_terms: D000818:Animals; D062186:Arterial Pressure / Q000502:physiology; D002478:Cells, Cultured; D019332:Endothelin-1 / Q000378:metabolism; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism*; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D006973:Hypertension / Q000378:metabolism / Q000503:physiopathology; D033461:Hyperuricemia / Q000378:metabolism / Q000503:physiopathology; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance / Q000502:physiology*; D008297:Male; D009569:Nitric Oxide / Q000378:metabolism*; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation / Q000502:physiology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D014527:Uric Acid / Q000494:pharmacology*; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology
chemical_list: D019332:Endothelin-1; D007328:Insulin; D014527:Uric Acid; D009569:Nitric Oxide; D052250:Nitric Oxide Synthase Type III; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt
keywords: eNOS; hypertension