Hypertension, Vol 21, 925-928, Copyright © 1993 by American Heart Association
HL Jackman, PW Morris, SF Rabito, GB Johansson, RA Skidgel and EG Erdos
We previously investigated the inactivation of endothelin-1 by deamidase
(lysosomal protective protein), present in many cells, including vascular
smooth muscle cells. This enzyme, which we originally purified from human
platelets, preferentially hydrolyzes peptides at the C-terminus with
hydrophobic amino acids in the P1 or P1' position or both and thereby
inactivates endothelin-1, which has a C-terminal sequence of
Ile19-Ile20-Trp21-OH. We tested for the presence of deamidase in cultured
bovine aortic endothelial cells. The final supernatant of the homogenized
cells (S3) cleaved the deamidase substrate dansyl-Phe-Leu-Arg at a rate of
1.3 nmol/min per 10(6) cells at pH 5.5 at 37 degrees C. Endothelin-1 was
completely inactivated by the S3 fraction as determined on rat thoracic
aorta strips. The major site of inactivation was the Ile20-Trp21 bond,
established by high performance liquid chromatography and by amino acid
analysis where the main product was des-Trp21-endothelin-1. The hydrolysis
of endothelin-1 (5.9 nmol/min per milligram of protein at pH 5.5 at 23
degrees C) by S3 was blocked mainly by inhibitors of deamidase, including
diisopropyl fluorophosphate, but not by inhibitors of some other
peptidases. This is the first report of a novel pathway of endothelin-1
metabolism in endothelial cells. Thus, endothelial cells, besides being the
source of endothelin-1, contain an enzyme that inactivates it.
ARTICLES
Inactivation of endothelin-1 by an enzyme of the vascular endothelial cells
Laboratory of Peptide Research, University of Illinois College of Medicine, Chicago 60612.
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