title: 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.affiliation: *College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Department of Obstetrics and Gynecology, Seoul National University College of Medicine and Department of Obstetrics and Gynecology, Seoul Metropolitan Government Seoul National University Boramae Medical Center, Seoul, Republic of Korea.
authors.forename: You-Jin
authors.initials: YJ
authors.lastname: Choi
authors.affiliation: *College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Department of Obstetrics and Gynecology, Seoul National University College of Medicine and Department of Obstetrics and Gynecology, Seoul Metropolitan Government Seoul National University Boramae Medical Center, Seoul, Republic of Korea.
authors.forename: Yujin
authors.initials: Y
authors.lastname: Yoon
authors.affiliation: *College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Department of Obstetrics and Gynecology, Seoul National University College of Medicine and Department of Obstetrics and Gynecology, Seoul Metropolitan Government Seoul National University Boramae Medical Center, Seoul, Republic of Korea.
authors.forename: Kang-Yo
authors.initials: KY
authors.lastname: Lee
authors.affiliation: *College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Department of Obstetrics and Gynecology, Seoul National University College of Medicine and Department of Obstetrics and Gynecology, Seoul Metropolitan Government Seoul National University Boramae Medical Center, Seoul, Republic of Korea.
authors.forename: Yun-Pyo
authors.initials: YP
authors.lastname: Kang
authors.affiliation: *College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Department of Obstetrics and Gynecology, Seoul National University College of Medicine and Department of Obstetrics and Gynecology, Seoul Metropolitan Government Seoul National University Boramae Medical Center, Seoul, Republic of Korea.
authors.forename: Dong Kyu
authors.initials: DK
authors.lastname: Lim
authors.affiliation: *College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Department of Obstetrics and Gynecology, Seoul National University College of Medicine and Department of Obstetrics and Gynecology, Seoul Metropolitan Government Seoul National University Boramae Medical Center, Seoul, Republic of Korea.
authors.forename: Sung Won
authors.initials: SW
authors.lastname: Kwon
authors.affiliation: *College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Department of Obstetrics and Gynecology, Seoul National University College of Medicine and Department of Obstetrics and Gynecology, Seoul Metropolitan Government Seoul National University Boramae Medical Center, Seoul, Republic of Korea.
authors.forename: Keon-Wook
authors.initials: KW
authors.lastname: Kang
authors.affiliation: *College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Department of Obstetrics and Gynecology, Seoul National University College of Medicine and Department of Obstetrics and Gynecology, Seoul Metropolitan Government Seoul National University Boramae Medical Center, Seoul, Republic of Korea *College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Department of Obstetrics and Gynecology, Seoul National University College of Medicine and Department of Obstetrics and Gynecology, Seoul Metropolitan Government Seoul National University Boramae Medical Center, Seoul, Republic of Korea.
authors.forename: Seung-Mi
authors.initials: SM
authors.lastname: Lee
authors.affiliation: *College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Department of Obstetrics and Gynecology, Seoul National University College of Medicine and Department of Obstetrics and Gynecology, Seoul Metropolitan Government Seoul National University Boramae Medical Center, Seoul, Republic of Korea lee@snu.ac.kr.
authors.forename: Byung-Hoon
authors.initials: BH
authors.lastname: Lee
mesh_terms: D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D006973:Hypertension / Q000139:chemically induced*; D007328:Insulin / Q000494:pharmacology; D008687:Metformin / Q000494:pharmacology; D009569:Nitric Oxide / Q000096:biosynthesis; D052250:Nitric Oxide Synthase Type III / Q000096:biosynthesis* / Q000378:metabolism; D009963:Orotic Acid / Q000633:toxicity*; D010766:Phosphorylation
chemical_list: D007328:Insulin; D009569:Nitric Oxide; D009963:Orotic Acid; D008687:Metformin; D052250:Nitric Oxide Synthase Type III
keywords: eNOS; endothelial dysfunction; hypertension; insulin resistance; orotic acid