Ruschitzka F, Moehrlen U, Quaschning T, Lachat M, Noll G, Shaw S, Yang Z, Teupser D, Subkowski T, Turina M I, Lüscher T F
Cardiology, University Hospital and Cardiovascular Research, Institute of Physiology, University of Zürich, Switzerland.
Circulation. 2000 Sep 5;102(10):1086-92. doi: 10.1161/01.cir.102.10.1086.
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.
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).
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.
内皮素转换酶（ECEs）是生成内皮素-1（ET-1）的关键酶。然而，它们在心血管疾病患者中的病理生理作用仍不明确。
在患有已明确心血管危险因素的冠心病患者的乳内动脉（IMA，n = 33）和大隐静脉（SV，n = 27）中检测血管对大内皮素-1（bigET-1；10⁻⁹至10⁻⁷mol/L）和ET-1（10⁻⁹至10⁻⁷mol/L）的反应性。通过将外源性添加的bigET-1转化为ET-1来测定血管ECE活性。通过放射免疫分析法测量bigET-1和ET-1的组织含量。此外，通过蛋白质印迹分析测定低密度脂蛋白（LDL）和氧化型LDL对人IMA内皮细胞中ECE-1蛋白水平的影响。在IMA中，血管ECE活性与血清LDL水平呈负相关（r = -0.76；P < 0.01），与收缩压和舒张压呈负相关，与纤维蛋白原呈正相关（r = 0.58；P < 0.05）。在SV中，纤维蛋白原是唯一与血管ECE活性相关的参数。高纤维蛋白原血症患者的IMA中bigET-1的血管组织含量降低，但收缩压升高和血清LDL水平升高的患者中bigET-1的血管组织含量增加（P < 0.05）。最有趣的是，LDL和氧化型LDL下调人IMA内皮细胞中ECE-1蛋白水平（P < 0.05）。
这些数据首次表明，血管ECE活性（1）与血清LDL水平和血压呈负相关，（2）与人血管组织中的纤维蛋白原呈正相关。因此，ECE-1活性可能调节冠心病患者的心血管风险。
