doi: 10.1161/hq0202.103994
© 2002 American Heart Association, Inc.
Vascular Biology |
Activated Mast Cells Increase the Level of Endothelin-1 mRNA in Cocultured Endothelial Cells and Degrade the Secreted Peptide
From the Unit of Clinical Physiology (K.P.M., O.S., T.N., F.Y.F.), Minerva Foundation Institute for Medical Research, Helsinki; the Department of Internal Medicine (K.P.M.), Turku University Central Hospital, Turku; the Wihuri Research Institute (P.V.-H., P.T.K., Y.W.), Helsinki; the Department of Internal Medicine (O.S., F.Y.F.) and the Division of Rheumatology, Department of Internal Medicine (K.K.E.), Helsinki University Central Hospital, Helsinki; and the Department of Protein Chemistry (M.B.), Institute of Biomedicine, Helsinki University, Helsinki, Finland.
Correspondence to Petri T Kovanen, MD, Wihuri Research Institute, Kalliolinnantie 4, 00140 Helsinki, Finland. E-mail petri.kovanen{at}wri.fi
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.
Key Words: endothelin-1 • endothelium • mast cells • chymase • carboxypeptidase A
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