title: Ursodeoxycholic acid inhibits endothelin-1 production in human vascular endothelial cells.
abstract: Endothelin-1 is known to be implicated in the pathogenesis of hepatobiliary diseases such as cirrhosis, especially in portal hypertension. This study aimed to investigate the effects of ursodeoxycholic acid on endothelin-1 production in human endothelial cells. The effects of ursodeoxycholic acid and its conjugates (tauroursodeoxycholic and glycoursodeoxycholic acids) on endothelin-1 production as well as nitric oxide (NO) in human umbilical vein endothelial cells (HUVECs) were examined. The production of endothelin-1 and nitric oxide in culture medium was measured using enzyme-linked immunosorbent assay (ELISA) and the Griess method, respectively. Endothelin-1 and endothelial nitric oxide synthase (eNOS) mRNA expression were investigated by real-time quantitative reverse transcriptase/polymerase chain reaction (RT-PCR). Ursodeoxycholic acid (30-1000 microM) inhibited endothelin-1 production in a concentration-dependent manner, and ursodeoxycholic acid at concentrations higher than 300 microM increased nitric oxide production in culture medium. The conjugates of ursodeoxycholic acid also increased nitric oxide production and decreased endothelin-1 production, which was less effective than ursodeoxycholic acid. N-nitro-L-arginine-mythel-ester (L-NAME), a nitric oxide synthase (NOS) inhibitor, suppressed the ursodeoxycholic acid-induced nitric oxide production, but it did not antagonize the inhibitory effects of ursodeoxycholic acid on endothelin-1 production. Ursodeoxycholic acid also induced a concentration-dependent decrease in endothelin-1 mRNA expression without significant changes in eNOS mRNA expression. These results provide novel evidence that ursodeoxycholic acid inhibits endothelin-1 production in human endothelial cells, but nitric oxide is not responsible for the inhibitory effect of ursodeoxycholic acid on endothelin-1. Thus, ursodeoxycholic acid therapy may prevent the development of several pathogenesis such as portal hypertension observed in patients with cirrhosis due to the improvement of endothelial function.
authors.affiliation: Department of Cardiovascular Medicine, Respiratory Medicine, and Gastroenterology, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8645, Japan.
authors.forename: Ji
authors.initials: J
authors.lastname: Ma
authors.forename: Haruko
authors.initials: H
authors.lastname: Iida
authors.forename: Taisuke
authors.initials: T
authors.lastname: Jo
authors.forename: Haruhito
authors.initials: H
authors.lastname: Takano
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Oonuma
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Morita
authors.forename: Teruhiko
authors.initials: T
authors.lastname: Toyo-Oka
authors.forename: Masao
authors.initials: M
authors.lastname: Omata
authors.forename: Ryozo
authors.initials: R
authors.lastname: Nagai
authors.forename: Yukichi
authors.initials: Y
authors.lastname: Okuda
authors.forename: Nobuhiro
authors.initials: N
authors.lastname: Yamada
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Nakajima
mesh_terms: D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism; D019332:Endothelin-1 / Q000096:biosynthesis* / Q000235:genetics; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004797:Enzyme-Linked Immunosorbent Assay; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000096:biosynthesis; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000235:genetics; D052250:Nitric Oxide Synthase Type III; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014580:Ursodeoxycholic Acid / Q000494:pharmacology*
chemical_list: D019332:Endothelin-1; D004791:Enzyme Inhibitors; D012333:RNA, Messenger; D009569:Nitric Oxide; D014580:Ursodeoxycholic Acid; C496314:NOS3 protein, human; D019001:Nitric Oxide Synthase; D052250:Nitric Oxide Synthase Type III; D019331:NG-Nitroarginine Methyl Ester