Orotic acid induces hypertension associated with impaired endothelial nitric oxide synthesis

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

Research output: Contribution to journalArticle

5 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)307-317
Number of pages11
JournalToxicological Sciences
Volume144
Issue number2
DOIs
StatePublished - Apr 1 2015

Fingerprint

Orotic Acid
Nitric Oxide
Insulin
Hypertension
Metformin
Nitric Oxide Synthase
Insulin Resistance
Phosphorylation
AMP-Activated Protein Kinases
1-Phosphatidylinositol 4-Kinase
Phosphatidylinositols
Rats
Pyrimidine Nucleotides
Blood Pressure
Proto-Oncogene Proteins c-akt
Nitric Oxide Synthase Type III
Biosynthesis
Endothelial cells
Human Umbilical Vein Endothelial Cells
Blood pressure

Keywords

  • Endothelial dysfunction
  • ENOS
  • Hypertension
  • Insulin resistance
  • Orotic acid

ASJC Scopus subject areas

  • Toxicology

Cite this

Choi, Y. J., Yoon, Y., Lee, K. Y., Kang, Y. P., Lim, D. K., Kwon, S. W., ... Lee, B. H. (2015). Orotic acid induces hypertension associated with impaired endothelial nitric oxide synthesis. Toxicological Sciences, 144(2), 307-317. https://doi.org/10.1093/toxsci/kfv00

Orotic acid induces hypertension associated with impaired endothelial nitric oxide synthesis. / Choi, You Jin; Yoon, Yujin; Lee, Kang Yo; Kang, Yun Pyo; Lim, Dong Kyu; Kwon, Sung Won; Kang, Keon Wook; Lee, Seung Mi; Lee, Byung Hoon.

In: Toxicological Sciences, Vol. 144, No. 2, 01.04.2015, p. 307-317.

Research output: Contribution to journalArticle

Choi, YJ, Yoon, Y, Lee, KY, Kang, YP, Lim, DK, Kwon, SW, Kang, KW, Lee, SM & Lee, BH 2015, 'Orotic acid induces hypertension associated with impaired endothelial nitric oxide synthesis', Toxicological Sciences, vol. 144, no. 2, pp. 307-317. https://doi.org/10.1093/toxsci/kfv00
Choi, You Jin ; Yoon, Yujin ; Lee, Kang Yo ; Kang, Yun Pyo ; Lim, Dong Kyu ; Kwon, Sung Won ; Kang, Keon Wook ; Lee, Seung Mi ; Lee, Byung Hoon. / Orotic acid induces hypertension associated with impaired endothelial nitric oxide synthesis. In: Toxicological Sciences. 2015 ; Vol. 144, No. 2. pp. 307-317.
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