TY - JOUR
T1 - Modulation of functionally active endothelin-converting enzyme by chrome neutral endopeptidase inhibition in experimental atherosclerosis
AU - Grantham, J. Aaron
AU - Schirger, John A.
AU - Wennberg, Paul W.
AU - Sandberg, Sharon
AU - Heublein, Denise M.
AU - Subkowski, Thomas
AU - Burnett, John C.
PY - 2000/4/25
Y1 - 2000/4/25
N2 - 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.
AB - 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.
KW - Atherosclerosis
KW - Endothelin
KW - Natriuretic peptides
KW - Vasoconstriction
UR - http://www.scopus.com/inward/record.url?scp=0034712692&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0034712692&partnerID=8YFLogxK
U2 - 10.1161/01.CIR.101.16.1976
DO - 10.1161/01.CIR.101.16.1976
M3 - Article
C2 - 10779465
AN - SCOPUS:0034712692
SN - 0009-7322
VL - 101
SP - 1976
EP - 1981
JO - Circulation
JF - Circulation
IS - 16
ER -