(Circulation. 2000;101:1976.)
© 2000 American Heart Association, Inc.
Basic Science Reports |
Modulation of Functionally Active Endothelin-Converting Enzyme by Chronic Neutral Endopeptidase Inhibition in Experimental Atherosclerosis
From the Cardiorenal Research Laboratory, Division of Cardiovascular Diseases, Mayo Clinic, Rochester, Minn, and BASF Pharma (T.S.), Ludwigshafen, Germany.
Correspondence to J. Aaron Grantham, MD, Cardiorenal Research Laboratory, Mayo Clinic, 200 First St SW, Rochester, MN 55905. E-mail grantham.aaron{at}mayo.edu
Background—Endothelin-converting
enzyme-1 (ECE-1) processes big endothelin-1 (ET-1) to ET-1, a peptide
implicated in atheroma formation. ECE-1 exists in 2
isoforms (ECE-1
and ECE-1ß), the result of alternative splicing of
a common gene. Neutral endopeptidase (NEP) is a
genetically distinct metallopeptidase that degrades the
natriuretic peptides. These peptides mediate
antiproliferative and vasodilating actions. We sought to demonstrate
the distribution of the 2 ECE-1 isoforms in experimental
atherosclerosis, to determine the effects of chronic
NEP-I on plasma cGMP concentrations, vascular wall ECE-1 activity, and
ET-1 concentration, and to correlate these actions with
atheroma formation. Our hypothesis was that chronic NEP-I,
in association with augmented cGMP, would inhibit ECE-1 conversion of
big ET-1 to active ET-1, thus reducing tissue ET-1 concentrations and
associated atheroma formation.
Methods and Results—Cholesterol-fed New Zealand White
rabbits (n=8, 1% cholesterol diet) and NEP-I–treated
cholesterol-fed New Zealand White rabbits (n=8;
candoxatril, 30 mg/kg per day, Pfizer) were euthanized after 8 weeks of
feeding. ECE-1 and ECE-1ß immunoreactivity was present in the
aortas of both groups. Compared with control values, plasma cGMP
concentrations were increased (2.8±0.6 versus 8.4±1.2 pmol/mL,
P<0.05), ECE-1 activity was attenuated (68±3% versus
32±8%, P<0.05), aortic tissue ET-1 concentrations
were reduced (4.6±0.5 versus 3.2±0.3 pg/mg protein,
P<0.05), and atheroma formation was
attenuated (62±6% versus 34±5%, P<0.01) by
NEP-I.
Conclusions—These studies suggest that ECE-1 is present and functionally active in the vascular wall in atherosclerosis. Inhibition of ECE-1 by NEP-I represents a novel approach to interruption of the endothelin system in this cardiovascular disease state.
Key Words: atherosclerosis • endothelin • natriuretic peptides • vasoconstriction
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