期刊论文详细信息
Modulation of functionally active endothelin-converting enzyme by chronic neutral endopeptidase inhibition in experimental atherosclerosis
Article
关键词: ATRIAL-NATRIURETIC-PEPTIDE;    SMOOTH-MUSCLE CELLS;    LOW-DENSITY-LIPOPROTEIN;    MESSENGER-RNA;    FED RABBITS;    EXPRESSION;    CHOLESTEROL;    SUPPRESSION;    SECRETION;    MACROPHAGES;   
DOI  :  10.1161/01.CIR.101.16.1976
来源: SCIE
【 摘 要 】

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 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 alpha and ECE-1 beta 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.

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