title: Effects of Uric Acid on the NO Production of HUVECs and its Restoration by Urate Lowering Agents.
abstract: BACKGROUND
  Although urate impaired the endothelial function, its underlying mechanism remains unknown. We hypothesized that urate impaired nitric oxide (NO) production in human umbilical vein endothelial cells (HUVECs) via activation of uric acid transporters (UATs).
  
  
  OBJECTIVE
  In the present study, we studied effects of urate on NO production and eNOS protein expression in HUVEC cells in the presence and absence of urate lowering agents using molecular biological and biochemical assays.
  
  
  RESULTS
  HUVECs expressed the 4 kinds of UATs, URATv1, ABCG2, MRP4 and MCT9. Exposure to urate at 7 mg/dl for 24 h significantly reduced production of NO. Pretreatment with benzbromarone, losartan or irbesartan normalized NO production. The same exposure resulted in dephosphorylation of endothelial NO synthase (eNOS) in HUVECs. Again pretreatment with benzbromarone, losartan or irbesartan abolished this effect.
  
  
  CONCLUSIONS
  Urate reduced NO production by impaired phosphorylation of eNOS in HUVEC via activation of UATs, which could be normalized by urate lowering agents.
authors.affiliation: Division of Regenerative Medicine and Therapeutics, Institute of Regenerative Medicine and Biofunction, Graduate School of Medical Sciences, Tottori University, Yonago, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Mishima
authors.affiliation: Department of Regional Medicine, Tottori University Faculty of Medicine, Yonago, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Hamada
authors.affiliation: Division of Regenerative Medicine and Therapeutics, Institute of Regenerative Medicine and Biofunction, Graduate School of Medical Sciences, Tottori University, Yonago, Japan.
authors.forename: N
authors.initials: N
authors.lastname: Maharani
authors.affiliation: Division of Regenerative Medicine and Therapeutics, Institute of Regenerative Medicine and Biofunction, Graduate School of Medical Sciences, Tottori University, Yonago, Japan.
authors.forename: N
authors.initials: N
authors.lastname: Ikeda
authors.affiliation: Division of Organ Regeneration Surgery, Tottori University Faculty of Medicine, Yonago, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Onohara
authors.affiliation: Division of Regenerative Medicine and Therapeutics, Institute of Regenerative Medicine and Biofunction, Graduate School of Medical Sciences, Tottori University, Yonago, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Notsu
authors.affiliation: Department of Biological Regulation, Tottori University Faculty of Medicine, Yonago, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Ninomiya
authors.affiliation: Division of Cardiovascular Medicine, Fujii Masao Memorial Hospital, Kurayoshi, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Miyazaki
authors.affiliation: Department of Cardiovascular Medicine, Sanin Rosai Hospital, Yonago, Japan.
authors.forename: E
authors.initials: E
authors.lastname: Mizuta
authors.affiliation: Division of Cardiovascular Medicine Department of Molecular Medicine and Therapeutics, Tottori University Faculty of Medicine, Yonago, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Sugihara
authors.affiliation: Division of Cardiovascular Medicine Department of Molecular Medicine and Therapeutics, Tottori University Faculty of Medicine, Yonago, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Kato
authors.affiliation: Department of Clinical Laboratory, Tottori University Hospital, Yonago, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Ogino
authors.affiliation: Department of Cardiology, Toranomon Hospital, Tokyo, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Kuwabara
authors.affiliation: Department of Surgery, Tomimasu Surgical and Primary Care Clinic, Yonago, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Hirota
authors.affiliation: Division of Regenerative Medicine and Therapeutics, Institute of Regenerative Medicine and Biofunction, Graduate School of Medical Sciences, Tottori University, Yonago, Japan.
authors.forename: A
authors.initials: A
authors.lastname: Yoshida
authors.affiliation: Department of Pharmacology, Dokkyo Medical College, Tochigi, Japan.
authors.forename: N
authors.initials: N
authors.lastname: Otani
authors.affiliation: Department of Pharmacology, Dokkyo Medical College, Tochigi, Japan.
authors.forename: N
authors.initials: N
authors.lastname: Anzai
authors.affiliation: Division of Regenerative Medicine and Therapeutics, Institute of Regenerative Medicine and Biofunction, Graduate School of Medical Sciences, Tottori University, Yonago, Japan.
authors.forename: I
authors.initials: I
authors.lastname: Hisatome
mesh_terms: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2 / Q000037:antagonists & inhibitors / Q000378:metabolism; D001553:Benzbromarone / Q000494:pharmacology; D001713:Biphenyl Compounds / Q000494:pharmacology; D002478:Cells, Cultured; D051246:Glucose Transport Proteins, Facilitative / Q000037:antagonists & inhibitors / Q000378:metabolism; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D000077405:Irbesartan; D019808:Losartan / Q000494:pharmacology; D027501:Monocarboxylic Acid Transporters / Q000037:antagonists & inhibitors / Q000378:metabolism; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism*; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism*; D010766:Phosphorylation; D013777:Tetrazoles / Q000494:pharmacology; D014527:Uric Acid / Q000494:pharmacology*; D014528:Uricosuric Agents / Q000494:pharmacology*
chemical_list: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D001553:Benzbromarone; D001713:Biphenyl Compounds; D051246:Glucose Transport Proteins, Facilitative; D000077405:Irbesartan; D019808:Losartan; D027501:Monocarboxylic Acid Transporters; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D009363:Neoplasm Proteins; D009569:Nitric Oxide; D052250:Nitric Oxide Synthase Type III; D013777:Tetrazoles; D014527:Uric Acid; D014528:Uricosuric Agents; C073492:ABCC4 protein, human; C116614:ABCG2 protein, human; C549233:SLC16A9 protein, human; C411811:SLC2A9 protein, human; C496314:NOS3 protein, human