title: Endothelin-1 is induced by cytokines in human vascular smooth muscle cells: evidence for intracellular endothelin-converting enzyme.
abstract: Endothelin-1 (ET-1) is the predominant endothelin isopeptide generated by the vascular wall and therefore appears to be the most important peptide involved in regulation of cardiovascular events. Many pathologic conditions are associated with elevations of ET-1 in the blood vessel wall. Because these conditions are often cytokine driven, we examined the effects of a mixture of cytokines on ET-1 production in human vascular smooth muscle cells (VSMCs) derived from internal mammary artery and saphenous vein (SV). Incubation of IMA and SV VSMCs with tumor necrosis factor-alpha (10 ng/ml) and interferon-gamma (1000 U/ml) in combination for up to 48 h markedly elevated the expression of mRNA for prepro-ET-1 and the release of ET-1 into the culture medium. This cytokine-stimulated release of ET-1 was inhibited by a series of dual endothelin-converting enzyme (ECE)/neutral endopeptidase inhibitors, phosphoramidon, CGS 26303, and CGS 26393, with an accompanying increase in big ET-1 release but with no effect on expression of mRNA for prepro-ET-1. These same compounds were 10 times more potent at inhibiting the conversion of exogenously applied big ET-1 to ET-1. ECE-1b/c mRNA is present in SV VSMCs, however no ECE-1a is present in these cells. Thus VSMCs most probably contain, like endothelial cells, an intracellular ECE responsible for the endogenous synthesis of ET-1. Under the influence of pro-inflammatory mediators the vascular smooth muscle can therefore become an important site of ET-1 production, as has already been established for the dilator mediators nitric oxide, prostaglandin I2, and prostaglandin E2.
authors.affiliation: Vascular Inflammation, The William Harvey Research Institute, St. Bartholomew's and the Royal London School of Medicine and Dentistry, Charterhouse Square, London, United Kingdom.
authors.forename: M
authors.initials: M
authors.lastname: Woods
authors.forename: J A
authors.initials: JA
authors.lastname: Mitchell
authors.forename: E G
authors.initials: EG
authors.lastname: Wood
authors.forename: S
authors.initials: S
authors.lastname: Barker
authors.forename: N R
authors.initials: NR
authors.lastname: Walcot
authors.forename: G M
authors.initials: GM
authors.lastname: Rees
authors.forename: T D
authors.initials: TD
authors.lastname: Warner
mesh_terms: D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors / Q000302:isolation & purification*; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism*; D004347:Drug Interactions; D019332:Endothelin-1 / Q000096:biosynthesis / Q000378:metabolism*; D000072396:Endothelin-Converting Enzymes; D006020:Glycopeptides / Q000494:pharmacology; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D008323:Mammary Arteries / Q000201:enzymology / Q000378:metabolism; D008666:Metalloendopeptidases; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000201:enzymology* / Q000378:metabolism; D063065:Organophosphonates / Q000494:pharmacology; D010649:Phenylalanine / Q000031:analogs & derivatives / Q000494:pharmacology; D011480:Protease Inhibitors / Q000494:pharmacology; D012333:RNA, Messenger / Q000096:biosynthesis; D012501:Saphenous Vein / Q000201:enzymology / Q000378:metabolism; D013777:Tetrazoles / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: C086164:CGS 24592; D016207:Cytokines; D019332:Endothelin-1; D006020:Glycopeptides; D063065:Organophosphonates; D011480:Protease Inhibitors; D012333:RNA, Messenger; D013777:Tetrazoles; D014409:Tumor Necrosis Factor-alpha; C089987:CGS 26303; C098285:CGS 26393; D010649:Phenylalanine; D007371:Interferon-gamma; D016282:Aspartic Acid Endopeptidases; D008666:Metalloendopeptidases; D000072396:Endothelin-Converting Enzymes; C008890:phosphoramidon