Orotic acid induces hypertension associated with impaired endothelial nitric oxide synthesis.

Abstract

Orotic acid (OA) is an intermediate of pyrimidine nucleotide biosynthesis. Hereditary deficiencies in some enzymes associated with pyrimidine synthesis or the urea cycle induce OA accumulation, resulting in orotic aciduria. A link between patients with orotic aciduria and hypertension has been reported; however, the molecular mechanisms remain elusive. In this study, to elucidate the role of OA in vascular insulin resistance, we investigated whether OA induced endothelial dysfunction and hypertension. OA inhibited insulin- or metformin-stimulated nitric oxide (NO) production and endothelial NO synthase (eNOS) phosphorylation in human umbilical vein endothelial cells. A decreased insulin response by OA was mediated by impairment of the insulin-stimulated phosphoinositide 3-kinase (PI3K)-protein kinase B (PKB/Akt) signaling pathway in cells overexpressing the p110-PI3K catalytic subunit. Impaired effects of metformin on eNOS phosphorylation and NO production were reversed in cells transfected with constitutively active AMP-activated protein kinase. Moreover, experimental induction of orotic aciduria in rats caused insulin resistance, measured as a 125% increase in the homeostasis model assessment, and hypertension, measured as a 25% increase in systolic blood pressure. OA increased the plasma concentration of endothelin-1 by 201% and significantly inhibited insulin- or metformin-induced vasodilation. A compromised insulin or metformin response on the Akt/eNOS and AMP-activated protein kinase/eNOS pathway was observed in aortic rings of OA-fed rats. Taken together, we showed that OA induces endothelial dysfunction by contributing to vascular and systemic insulin resistance that affects insulin- or metformin-induced NO production, leading to the development of hypertension.

• Authors: You-Jin Choi, Yujin Yoon, Kang-Yo Lee, Yun-Pyo Kang, Dong Kyu Lim, Sung Won Kwon, Keon-Wook Kang, Seung-Mi Lee, Byung-Hoon Lee
• Journal: Toxicological sciences : an official journal of the Society of Toxicology (Toxicol Sci) Vol. 144 Issue 2 Pg. 307-17 (Apr 2015) ISSN: 1096-0929 [Electronic] United States
• PMID: 25601987 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © The Author 2015. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please e-mail: [email protected].

Chemical References

• Insulin
• Nitric Oxide
• Orotic Acid
• Metformin
• Nitric Oxide Synthase Type III

Topics

• Human Umbilical Vein Endothelial Cells
• Humans
• Hypertension (chemically induced)
• Insulin (pharmacology)
• Metformin (pharmacology)
• Nitric Oxide (biosynthesis)
• Nitric Oxide Synthase Type III (biosynthesis, metabolism)
• Orotic Acid (toxicity)
• Phosphorylation