Affiliation:
1. From the Cardiorenal Research Laboratory, Division of Cardiovascular Diseases, Mayo Clinic, Rochester, Minn, and BASF Pharma (T.S.), Ludwigshafen, Germany.
Abstract
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-1α and ECE-1β), 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-1α and ECE-1β 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.
Publisher
Ovid Technologies (Wolters Kluwer Health)
Subject
Physiology (medical),Cardiology and Cardiovascular Medicine
Cited by
29 articles.
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