Expression of human endothelin-converting enzyme isoforms

A key step in endothelin-1 (ET-1) synthesis is the proteolytic cleavage of big ET-I 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 isofomis 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 I 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/mu g RNA), followed by ECE-1a (2.7 1.0 amol/mu g), ECE-1a (0.49 +/- 0.17 amol/pg), and ECE-1b (0.17 +/- 0.04 amol/mu g). 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-la. In addition, ECE-la mRNA expression was higher in patients receiving ACE-1 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.