Tissue endothelin-converting enzyme activity correlates with cardiovascular risk factors in coronary artery disease.
BACKGROUND
Endothelin-converting enzymes (ECEs) are the key enzymes in endothelin-1 (ET-1) generation. However, their pathophysiological role in patients with cardiovascular disease remains elusive.


RESULTS
Vascular reactivity to big endothelin-1 (bigET-1; 10(-9) to 10(-7) mol/L) and ET-1 (10(-9) to 10(-7) mol/L) were examined in the internal mammary artery (IMA, n=33) and saphenous vein (SV, n=27) of patients with coronary artery disease with identified cardiovascular risk factors. Vascular ECE activity was determined by conversion of exogenously added bigET-1 to ET-1. Tissue contents of bigET-1 and ET-1 were measured by radioimmunoassay. In addition, the effects of LDL and oxidized LDL on ECE-1 protein levels were determined by Western blot analysis in human IMA endothelial cells. In the IMA, vascular ECE activity showed an inverse correlation with serum LDL levels (r=-0.76; P<0.01) and systolic and diastolic blood pressure and a positive correlation with fibrinogen (r=0.58; P<0.05). In the SV, fibrinogen was the only parameter to be correlated with vascular ECE activity. Vascular tissue content of bigET-1 was attenuated in the IMA of patients with hyperfibrinogenemia but increased in patients with elevated systolic blood pressure and increased serum LDL levels (P<0.05). Most interestingly, LDL and oxidized LDL downregulated ECE-1 protein levels in human IMA endothelial cells (P<0.05).


CONCLUSIONS
These data demonstrate, for the first time, that vascular ECE activity is (1) inversely correlated with serum LDL levels and blood pressure and (2) positively associated with fibrinogen in human vascular tissue. Hence, ECE-1 activity may modulate cardiovascular risk in patients with coronary artery disease.
Ruschitzka
F
F
Cardiology, University Hospital and Cardiovascular Research, Institute of Physiology, University of Zürich, Switzerland.
Moehrlen
U
U
Quaschning
T
T
Lachat
M
M
Noll
G
G
Shaw
S
S
Yang
Z
Z
Teupser
D
D
Subkowski
T
T
Turina
M I
MI
Lüscher
T F
TF
D016282:Aspartic Acid Endopeptidases / Q000378:metabolism*; D001026:Coronary Artery Bypass; D003327:Coronary Disease / Q000201:enzymology* / Q000453:epidemiology*; D015536:Down-Regulation / Q000187:drug effects; D000072396:Endothelin-Converting Enzymes; D004730:Endothelium, Vascular / Q000166:cytology / Q000201:enzymology; D005260:Female; D006801:Humans; D008077:Lipoproteins, LDL / Q000097:blood / Q000494:pharmacology; D008297:Male; D008666:Metalloendopeptidases / Q000378:metabolism; D009569:Nitric Oxide / Q000097:blood; D010084:Oxidation-Reduction; D011725:Pyridines / Q000494:pharmacology; D012307:Risk Factors; D013237:Stereoisomerism
D008077:Lipoproteins, LDL; D011725:Pyridines; C099252:oxidized low density lipoprotein; D009569:Nitric Oxide; C086276:cerivastatin; D016282:Aspartic Acid Endopeptidases; D008666:Metalloendopeptidases; C000606923:ECE1 protein, human; D000072396:Endothelin-Converting Enzymes