Increased response to big endothelin-1 in atherosclerotic human coronary artery: functional evidence for up-regulation of endothelin-converting enzyme activity in disease.
Overproduction of the potent vasoconstrictor peptide endothelin-1 (ET-1) is implicated in the pathogenesis of coronary artery disease. In endothelium-denuded human coronary arteries the response to big ET-1 was significantly enhanced in atherosclerotic arteries (coronary artery disease, CAD; n=7) with an EC50 value of 96 nM (57- 161 nM, 95% C.I.) compared to 274 nM (205-365 nM) in non-diseased arteries (dilated cardiomyopathy, DCM; n=10) (Mann-Whitney U-test, P<0.05). Higher levels of immunoreactive endothelin (ET) could be detected by radioimmunoassay in bathing medium taken from CAD arteries than from DCM arteries (2.8+/-0.5 nM, n=5 vs 1.1+/-0.2 nM, n=7) (Student's two-tailed t-test, P<0.05). There were no differences in responses of arteries from either group to ET-1 (EC50 10 nM, CAD vs 14 nM, DCM). The enhanced response of atherosclerotic human coronary arteries to big ET-1 appears to be due to up-regulation of endothelin-converting enzyme (ECE) activity rather than to an augmented response of the arteries to ET-1. This non-endothelial ECE may therefore be an important therapeutic target in coronary artery disease.
Maguire
J J
JJ
Clinical Pharmacology Unit, University of Cambridge, Addenbrooke's Hospital.
Davenport
A P
AP
D000328:Adult; D016282:Aspartic Acid Endopeptidases / Q000378:metabolism*; D002311:Cardiomyopathy, Dilated / Q000201:enzymology; D003324:Coronary Artery Disease / Q000201:enzymology*; D003331:Coronary Vessels / Q000187:drug effects / Q000378:metabolism*; D019332:Endothelin-1; D000072396:Endothelin-Converting Enzymes; D016232:Endothelins / Q000494:pharmacology*; D004730:Endothelium, Vascular / Q000187:drug effects / Q000201:enzymology; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D006801:Humans; D008297:Male; D008666:Metalloendopeptidases; D008875:Middle Aged; D011498:Protein Precursors / Q000494:pharmacology*; D015854:Up-Regulation
D019332:Endothelin-1; D016232:Endothelins; D011498:Protein Precursors; D016282:Aspartic Acid Endopeptidases; D008666:Metalloendopeptidases; D000072396:Endothelin-Converting Enzymes