Human chymase, an enzyme forming novel bioactive 31-amino acid length endothelins.
We report the novel role of human chymase in the production of bioactive 31-amino acid length endothelins (ETs), which may play a role in allergies and vascular diseases. In the bronchi of asthmatic patients, the vascular tissue in atherosclerosis, and the heart muscle in cardiac hypertrophy, both ET-like immunoreactivity and the accumulation of mast cells significantly increase. Chymase from human mast cells selectively cleaves big ET-1, -2 and -3 at their Tyr31-Gly32 bonds, and produces novel bioactive 31-amino acid length ETs, ETs(1-31), without any further degradation products. However, chymases from other species, human cathepsin G, and porcine alpha-chymotrypsin, degrade big ETs. ETs(1-31) at concentrations between 10(-9) M and 10(-7) M exhibited various contractile potencies in rat tracheae and porcine coronary arteries in a dose-dependent manner. Furthermore, ET-1(1-31) at concentrations between 10(-14) M and 10(-10) M caused a significant increase in the intracellular free Ca2+ concentration. The contractile activity of ETs(1-31) may not be the consequence of conversion to the corresponding ETs(1-21) by phosphoramidon-sensitive ET converting enzyme(s) or other chymotrypsin-type proteases and metallo-endopeptidases, because the contractile activity was not significantly inhibited on treatment with inhibitors of these proteases prior to the addition of ET-1(1-31).
Kido
H
H
Division of Enzyme Chemistry, Institute for Enzyme Research, The University of Tokushima, Japan.
Nakano
A
A
Okishima
N
N
Wakabayashi
H
H
Kishi
F
F
Nakaya
Y
Y
Yoshizumi
M
M
Tamaki
T
T
D000818:Animals; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D002648:Child; D053818:Chymases; D003331:Coronary Vessels / Q000187:drug effects / Q000502:physiology; D016232:Endothelins / Q000096:biosynthesis*; D006801:Humans; D007424:Intracellular Fluid; D009119:Muscle Contraction / Q000502:physiology; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000502:physiology; D011480:Protease Inhibitors / Q000494:pharmacology; D051381:Rats; D012697:Serine Endopeptidases / Q000378:metabolism*; D013379:Substrate Specificity; D013552:Swine; D014132:Trachea / Q000187:drug effects / Q000502:physiology
D016232:Endothelins; D011480:Protease Inhibitors; D012697:Serine Endopeptidases; D053818:Chymases; D002118:Calcium