Modulation of functionally active endothelin-converting enzyme by chronic neutral endopeptidase inhibition in experimental atherosclerosis

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 alpha and ECE-1 beta) the result of alternative splici ng of a common gene. Neutral endopeptidase (NEP) is a genetically distinct metallopeptidase that degrades the natriuretic peptides. These peptides med iate antiproliferative and vasodilating actions. We sought to demonstrate t he distribution of the 2 ECE-1 isoforms in experimental atherosclerosis, to determine the effects of chronic NEP-I on plasma cGMP concentrations, vasc ular wall ECE-1 activity, and ET-1 concentration, and to correlate these ac tions with atheroma formation. Our hypothesis was that chronic NEP-I, in as sociation with augmented cGMP, would inhibit ECE-1 conversion of big ET-1 t o active ET-1, thus reducing tissue ET-1 concentrations and associated athe roma formation. Methods and Results-Cholesterol-fed New Zealand White rabbits (n=8, 1% chol esterol 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 o f feeding. ECE-1 alpha and ECE-1 beta immunoreactivity was present in the a ortas of both groups. Compared with control values, plasma cGMP concentrati ons were increased (2.8+/-0.6 versus 8.4+/-1.2 pmol/ml, P<0.05), ECE-1 acti vity was attenuated (68+/-3% versus 32+/-8%, P<0.05), aortic tissue ET-1 co ncentrations 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) b y NEP-I. Conclusions-These studies suggest that ECE-1 is present and functionally ac tive in the vascular wall in atherosclerosis. Inhibition of ECE-1 by NEP-I represents a novel approach to interruption of the endothelin system in thi s cardiovascular disease state.