title: Inhibitory effects of ursodeoxycholic acid on the induction of nitric oxide synthase in vascular smooth muscle cells.
abstract: The expression of inducible nitric oxide synthase (iNOS) and the resultant increased nitric oxide production are associated with endotoxemia and atherosclerotic lesions observed in transplant hearts or balloon-injured artery. Ursodeoxycholic acid has been shown to have cardiovascular protective effects, such as inhibition of the development of transplant arteriosclerosis, but its mechanism remains unclear. Here, we investigated the effects of ursodeoxycholic acid on nitric oxide production and the expression of iNOS in vascular smooth muscle cells isolated from adult rat aorta and rabbit coronary artery. Nitrite released from cells in the culture medium was measured with the Griess reaction. iNOS mRNA and protein were measured by Northern and Western blot analyses. Treatment with ursodeoxycholic acid (30-1000 microM) significantly inhibited lipopolysaccharide plus interferon-gamma-induced nitric oxide production in a concentration-dependent manner, but ursodeoxycholic acid showed only small inhibitory effects on nitric oxide production that had already been induced by lipopolysaccharide plus interferon-gamma. Ursodeoxycholic acid by itself did not affect basal nitric oxide production. Ursodeoxycholic acid also suppressed lipopolysaccharide plus interferon-gamma-induced expression of iNOS mRNA and protein. Ursodeoxycholic acid had the most potent inhibitory effect among various kinds of bile acids examined, i.e. chenodeoxycholic acid, deoxycholic acid, cholic acid and conjugated bile acids such as tauroursodeoxycholic acid. These results suggest that ursodeoxycholic acid inhibits the induction of iNOS and then nitric oxide production in aortic and coronary artery smooth muscle cells, suggesting a possible mechanism for the cardiovascular protective effect of ursodeoxycholic acid under various pathophysiological conditions such as endotoxemia and atherosclerosis.
authors.affiliation: Department of Cardiovascular, Respiratory Medicine and Gastroenterology, University of Tokyo, Graduate School of Medicine, 7-3-1 Hongo, Bunkyo, Japan.
authors.forename: Ji
authors.initials: J
authors.lastname: Ma
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Nakajima
authors.forename: Haruko
authors.initials: H
authors.lastname: Iida
authors.forename: Kuniaki
authors.initials: K
authors.lastname: Iwasawa
authors.forename: Kuniko
authors.initials: K
authors.lastname: Terasawa
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Oonuma
authors.forename: Taisuke
authors.initials: T
authors.lastname: Jo
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Morita
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Imuta
authors.forename: Jun ichi
authors.initials: Ji
authors.lastname: Suzuki
authors.forename: Ken
authors.initials: K
authors.lastname: Hirose
authors.forename: Yukichi
authors.initials: Y
authors.lastname: Okuda
authors.forename: Nobuhiko
authors.initials: N
authors.lastname: Yamada
authors.forename: Ryozo
authors.initials: R
authors.lastname: Nagai
authors.forename: Masao
authors.initials: M
authors.lastname: Omata
mesh_terms: D000818:Animals; D015152:Blotting, Northern; D015153:Blotting, Western; D004305:Dose-Response Relationship, Drug; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D007371:Interferon-gamma / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000235:genetics / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II; D012333:RNA, Messenger / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D011817:Rabbits; D051381:Rats; D017208:Rats, Wistar; D013997:Time Factors; D014580:Ursodeoxycholic Acid / Q000494:pharmacology*
chemical_list: D008070:Lipopolysaccharides; D012333:RNA, Messenger; D009569:Nitric Oxide; D014580:Ursodeoxycholic Acid; D007371:Interferon-gamma; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat