title: Activated mast cells increase the level of endothelin-1 mRNA in cocultured endothelial cells and degrade the secreted Peptide.
abstract: Subendothelial mast cells have been implicated in the pathogenesis of allergic inflammation, in atherosclerosis, and in the regulation of vascular tone. Because endothelin-1 (ET-1) is an important regulator of vascular tone and has also been implicated in the pathogenesis of atherosclerosis, we studied the role of mast cells in the metabolism of endothelial cell-derived ET-1. In mast cell-endothelial cell cocultures, activation of the mast cells with ensuing degranulation was accompanied by the increased expression of ET-1 mRNA in the endothelial cells, yet the immunoreactive ET-1 protein in the coculture medium disappeared almost completely during the 24-hour coculture. Activation of the mast cells with the ensuing degranulation resulted in proteolytic degradation of ET-1 by the 2 neutral proteases, chymase and carboxypeptidase A, of the exocytosed mast cell granules. With synthetic ET-1 and purified mast cell granule enzymes, efficient degradation of ET-1 by chymase and carboxypeptidase A was verified. These in vitro results imply a novel role for mast cell-derived neutral proteases in ET-1 metabolism and suggest that activated subendothelial mast cells are important local regulators of ET-1 metabolism.
authors.affiliation: Unit of Clinical Physiology, Minerva Foundation Institute for Medical Research, Helsinki, Finland.
authors.forename: Kaj P
authors.initials: KP
authors.lastname: Metsärinne
authors.forename: Pirjo
authors.initials: P
authors.lastname: Vehmaan-Kreula
authors.forename: Petri T
authors.initials: PT
authors.lastname: Kovanen
authors.forename: Outi
authors.initials: O
authors.lastname: Saijonmaa
authors.forename: Marc
authors.initials: M
authors.lastname: Baumann
authors.forename: Yenfeng
authors.initials: Y
authors.lastname: Wang
authors.forename: Tuulikki
authors.initials: T
authors.lastname: Nyman
authors.forename: Frej Y
authors.initials: FY
authors.lastname: Fyhrquist
authors.forename: Kari K
authors.initials: KK
authors.lastname: Eklund
mesh_terms: D000818:Animals; D002268:Carboxypeptidases / Q000037:antagonists & inhibitors / Q000378:metabolism; D043422:Carboxypeptidases A; D053818:Chymases; D018920:Coculture Techniques; D010450:Endopeptidases / Q000378:metabolism / Q000494:pharmacology; D019332:Endothelin-1 / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005089:Exocytosis; D006801:Humans; D008297:Male; D008407:Mast Cells / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D012697:Serine Endopeptidases / Q000378:metabolism
chemical_list: D019332:Endothelin-1; D004791:Enzyme Inhibitors; D012333:RNA, Messenger; D002268:Carboxypeptidases; D010450:Endopeptidases; D043422:Carboxypeptidases A; D012697:Serine Endopeptidases; D053818:Chymases