Tissue endothelin-converting enzyme activity correlates with cardiovascular risk factors in coronary artery disease

Background-Endothelin-converting enzymes (ECEs) are the key enzymes in endo thelin-l (ET-1) generation However, their pathophysiological role in patien ts with cardiovascular disease remains elusive. Methods and Results-Vascular reactivity to big endothelin-l (bigET-l; 10(-9 ) to 10(-7) mol/L) and ET-1 (10-9 to 10-7 mol/L) were examined in the inter nal mammary artery (IMA, n=33) and saphenous vein (SV, n=27) of patients wi th coronary artery disease with identified cardiovascular risk factors. Vas cular ECE activity was determined by conversion of exogenously added bigET- l to ET-1, Tissue contents of bigET-l and ET-1 were measured by radioimmuno assay, In addition, the effects of LDL and oxidized LDL on ECE-1 protein le vels were determined by Western blot analysis in human IMA endothelial cell s. In the IMA, vascular ECE activity showed an inverse correlation with ser um 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, fi brinogen was the only parameter to be correlated with vascular ECE activity . Vascular tissue content of bigET-l was attenuated in the IMA of patients with hyperfibrinogenemia but increased in patients with elevated systolic b lood pressure and increased serum LDL levels (P<0.05). Most interestingly, LDL and oxidized LDL downregulated ECE-1 protein levels in human IMA endoth elial cells (P<0.05), Conclusions-These data demonstrate, for the first time, that vascular ECE a ctivity is (1) inversely correlated with serum LDL levels and blood pressur e and (2) positively associated with fibrinogen in human vascular tissue, H ence, ECE-1 activity may modulate cardiovascular risk in patients with coro nary artery disease.