title: Endothelin B receptor antagonist increases preproendothelin-1 transcription in bovine aortic endothelial cells and in vivo.
abstract: Endothelin-1 (ET-1) receptor antagonists increase plasma immunoreactive ET-1 levels. However, their effect on preproendothelin-1 (PPE-1) mRNA levels is still controversial. Few studies have found a decrease in PPE-1 mRNA levels in endothelial cells treated with the nonselective ETA/B receptor antagonist, and others demonstrated that an ETB blockade by the selective antagonist BQ788 increases PPE-1 mRNA levels. We studied the effect of ETA and ETB selective receptor antagonists on PPE-1 transcription, both in vitro and in vivo. Endothelial cells, transiently transfected with PPE-1 luciferase plasmid, were treated with ET-1 receptor antagonists. Bosentan, a dual ETA/B receptor antagonist, and BQ788 (ETB receptor antagonist) treatment resulted in a 1.6-fold and 1.3-fold increase, respectively in luciferase activity as compared with the untreated control. In contrast, the ETA receptor antagonist, BQ123, had no effect on luciferase activity. Transgenic mice that express the luciferase gene under the control of PPE-1 promoter were treated with Bosentan. Luciferase activity, PPE-1 mRNA levels, and plasma immunoreactive ET-1 levels were increased by 1.6-fold to 2.0-fold in the Bosentan-treated group compared with the untreated, control group. ET-1 receptor blockade increased PPE-1 transcription both in vitro and in vivo. The increased transcription can be attributed to ETB receptor blockade, because BQ-788, but not BQ-123, increased PPE-1 transcription.
authors.affiliation: Institute of Lipid and Atherosclerosis Research, Sheba Medical Center, Tel Hashomer, Israel.
authors.forename: Michael
authors.initials: M
authors.lastname: Peled
authors.forename: Aviv
authors.initials: A
authors.lastname: Shaish
authors.forename: Liron
authors.initials: L
authors.lastname: Frishman
authors.forename: Hofit
authors.initials: H
authors.lastname: Cohen
authors.forename: Reshef
authors.initials: R
authors.lastname: Tal
authors.forename: Dror
authors.initials: D
authors.lastname: Harats
mesh_terms: D000818:Animals; D001011:Aorta; D000077300:Bosentan; D002417:Cattle; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism; D065130:Endothelin A Receptor Antagonists; D065131:Endothelin B Receptor Antagonists; D019332:Endothelin-1 / Q000096:biosynthesis* / Q000097:blood / Q000235:genetics / Q000276:immunology; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D008168:Lung / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009842:Oligopeptides / Q000494:pharmacology*; D010456:Peptides, Cyclic / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology*; D012333:RNA, Messenger / Q000032:analysis; D013449:Sulfonamides / Q000494:pharmacology; D014018:Tissue Distribution; D001616:beta-Galactosidase / Q000378:metabolism
chemical_list: D065130:Endothelin A Receptor Antagonists; D065131:Endothelin B Receptor Antagonists; D019332:Endothelin-1; D009842:Oligopeptides; D010456:Peptides, Cyclic; D010880:Piperidines; D012333:RNA, Messenger; D013449:Sulfonamides; C086539:BQ 788; D008156:Luciferases; D001616:beta-Galactosidase; D000077300:Bosentan; C072247:cyclo(Trp-Asp-Pro-Val-Leu)