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: You-Jin Choi, Yujin Yoon, Kang-Yo Lee, Tran Thi Hien, Keon Wook Kang, Kyong-Cheol Kim, Jeewoo Lee, Moo-Yeol Lee, Seung Mi Lee, Duk-Hee Kang, Byung-Hoon Lee
• Journal: FASEB journal : official publication of the Federation of American Societies for Experimental Biology (FASEB J) Vol. 28 Issue 7 Pg. 3197-204 (Jul 2014) ISSN: 1530-6860 [Electronic] United States
• PMID: 24652948 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © FASEB.

Chemical References

• Endothelin-1
• Insulin
• Uric Acid
• Nitric Oxide
• Nitric Oxide Synthase Type III
• Phosphatidylinositol 3-Kinases
• Proto-Oncogene Proteins c-akt

Topics

• Animals
• Arterial Pressure (physiology)
• Cells, Cultured
• Endothelin-1 (metabolism)
• Endothelium, Vascular (drug effects, metabolism)
• Human Umbilical Vein Endothelial Cells
• Humans
• Hypertension (metabolism, physiopathology)
• Hyperuricemia (metabolism, physiopathology)
• Insulin (metabolism)
• Insulin Resistance (physiology)
• Male
• Nitric Oxide (metabolism)
• Nitric Oxide Synthase Type III (metabolism)
• Phosphatidylinositol 3-Kinases (metabolism)
• Phosphorylation (physiology)
• Proto-Oncogene Proteins c-akt (metabolism)
• Rats
• Rats, Sprague-Dawley
• Uric Acid (pharmacology)
• Vasodilation (drug effects, physiology)