Minamino T, Kurihara H, Takahashi M, Shimada K, Maemura K, Oda H, Ishikawa T, Uchiyama T, Tanzawa K, Yazaki Y
Third Department of Internal Medicine, Faculty of Medicine, University of Tokyo, Japan.
Circulation. 1997 Jan 7;95(1):221-30. doi: 10.1161/01.cir.95.1.221.
Endothelin 1 has been implicated in various human diseases, including atherosclerosis. In this study, we examined the expression and localization of endothelin-converting enzyme-1 (ECE-1), the final key enzyme of endothelin 1 processing, in rat carotid arteries after balloon injury and in human coronary atherosclerotic lesions.
ECE-1 mRNA levels and ECE activity in rat balloon-injured arteries started to increase between 2 and 5 days after injury. The endothelin 1 content of tissue in injured arteries was concomitantly increased. Immunohistochemical staining located ECE-1 signals in endothelial cells in uninjured arteries, whereas ECE-1 immunoreactivity was detected in neointimal smooth muscle cells in injured arteries 5 to 14 days after balloon denudation. The size of the neointima was effectively reduced by phosphoramidon, an inhibitor of neutral metalloproteases, including ECE-1. In human coronary atherosclerotic lesions, intense ECE-1 immunoreactivity was detected in subsets of cells embedded in atheromatous plaque that correspond to smooth muscle cells and macrophages, as identified by staining for smooth muscle alpha-actin and CD68 surface marker, respectively.
The present study ascertained that ECE-1 is expressed in neointimal smooth muscle cells in rat balloon-injured arteries and in both smooth muscle cells and macrophages in human coronary atherosclerotic lesions. Blockade of ECE-1 was effective in reducing neointimal formation after balloon injury. Thus, ECE-1 may contribute to the process of injury-induced neointimal formation and atherosclerosis through the autocrine/paracrine effects of endothelin 1.
内皮素1与包括动脉粥样硬化在内的多种人类疾病有关。在本研究中，我们检测了内皮素转换酶-1（ECE-1）（内皮素1加工过程中的最终关键酶）在大鼠球囊损伤后颈动脉以及人类冠状动脉粥样硬化病变中的表达和定位。
大鼠球囊损伤动脉中ECE-1 mRNA水平和ECE活性在损伤后2至5天开始升高。损伤动脉组织中的内皮素1含量随之增加。免疫组织化学染色显示，在未损伤动脉的内皮细胞中可检测到ECE-1信号，而在球囊剥脱后5至14天的损伤动脉新生内膜平滑肌细胞中可检测到ECE-1免疫反应性。磷酰胺（一种包括ECE-1在内的中性金属蛋白酶抑制剂）可有效减小新生内膜的大小。在人类冠状动脉粥样硬化病变中，通过分别对平滑肌α-肌动蛋白和CD68表面标志物进行染色鉴定，在对应于平滑肌细胞和巨噬细胞的动脉粥样斑块中的部分细胞中检测到强烈的ECE-1免疫反应性。
本研究确定ECE-1在大鼠球囊损伤动脉的新生内膜平滑肌细胞以及人类冠状动脉粥样硬化病变的平滑肌细胞和巨噬细胞中均有表达。阻断ECE-1可有效减少球囊损伤后的新生内膜形成。因此，ECE-1可能通过内皮素1的自分泌/旁分泌作用参与损伤诱导的新生内膜形成和动脉粥样硬化过程。
