Goettsch W, Schubert A, Morawietz H
Department of Vascular Endothelium and Microcirculation, Medical Clinic and Policlinic III, University of Technology Dresden, Fetscherstr. 74, D-01307 Dresden, Germany.
Can J Physiol Pharmacol. 2008 Jun;86(6):299-309. doi: 10.1139/Y08-023.
A key step in endothelin-1 (ET-1) synthesis is the proteolytic cleavage of big ET-1 by the endothelin-converting enzyme-1 (ECE-1). Four alternatively spliced isoforms, ECE-1a to ECE-1d, have been discovered; however, regulation of the expression of specific ECE-1 isoforms is not well understood. Therefore, we stimulated primary human umbilical vein endothelial cells (HUVECs) with angiotensin II (Ang II). Furthermore, expression of ECE-1 isoforms was determined in internal mammary arteries of patients undergoing coronary artery bypass grafting surgery. Patients had received one of 4 therapies: angiotensin-converting enzyme inhibitors (ACE-I), Ang II type 1 receptor blockers (ARB), HMG-CoA reductase inhibitors (statins), and a control group that had received neither ACE-I, ARB (that is, treatment not interfering in the renin-angiotensin system), nor statins. Under control conditions, ECE-1a is the dominant isoform in HUVECs (4.5+/-2.8 amol/microg RNA), followed by ECE-1c (2.7+/-1.0 amol/microg), ECE-1d (0.49+/-0.17 amol/microg), and ECE-1b (0.17+/-0.04 amol/microg). Stimulation with Ang II did not change the ECE-1 expression pattern or the ET-1 release. We found that ECE-1 mRNA expression was higher in patients treated with statins than in patients treated with ARB therapy (5.8+/-0.76 RU versus 3.0+/-0.4 RU), mainly attributed to ECE-1a. In addition, ECE-1a mRNA expression was higher in patients receiving ACE-I therapy than in patients receiving ARB therapy (1.68+/-0.27 RU versus 0.83+/-0.07 RU). We conclude that ECE-1a is the major ECE-1 isoform in primary human endothelial cells. Its expression in internal mammary arteries can be regulated by statin therapy and differs between patients with ACE-I and ARB therapy.
内皮素 -1（ET -1）合成的关键步骤是内皮素转换酶 -1（ECE -1）对大内皮素 -1进行蛋白水解切割。现已发现四种可变剪接异构体，即ECE -1a至ECE -1d；然而，特定ECE -1异构体表达的调控机制尚不清楚。因此，我们用血管紧张素II（Ang II）刺激原代人脐静脉内皮细胞（HUVECs）。此外，还测定了接受冠状动脉搭桥手术患者的乳内动脉中ECE -1异构体的表达。患者接受了以下四种治疗之一：血管紧张素转换酶抑制剂（ACE -I）、1型血管紧张素II受体阻滞剂（ARB）、HMG -CoA还原酶抑制剂（他汀类药物），以及既未接受ACE -I、ARB（即不干扰肾素 - 血管紧张素系统的治疗）也未接受他汀类药物的对照组。在对照条件下，ECE -1a是HUVECs中的主要异构体（4.5±2.8 amol/μg RNA），其次是ECE -1c（2.7±1.0 amol/μg）、ECE -1d（0.49±0.17 amol/μg）和ECE -1b（0.17±0.04 amol/μg）。用Ang II刺激并未改变ECE -1的表达模式或ET -1的释放。我们发现，接受他汀类药物治疗的患者中ECE -1 mRNA表达高于接受ARB治疗的患者（5.8±0.76 RU对3.0±0.4 RU），主要归因于ECE -1a。此外，接受ACE -I治疗的患者中ECE -1a mRNA表达高于接受ARB治疗的患者（1.68±0.27 RU对0.83±0.07 RU）。我们得出结论，ECE -1a是原代人内皮细胞中的主要ECE -1异构体。其在乳内动脉中的表达可受他汀类药物治疗调控，且在接受ACE -I和ARB治疗的患者中有所不同。
