Ihling C, Göbel H R, Lippoldt A, Wessels S, Paul M, Schaefer H E, Zeiher A M
Department of Pathology, University of Freiburg, Germany.
J Pathol. 1996 Jul;179(3):303-8. doi: 10.1002/(SICI)1096-9896(199607)179:3<303::AID-PATH585>3.0.CO;2-9.
Endothelin (ET) is a very potent vasoconstrictor peptide, which was originally reported to be produced by endothelial cells and to act locally in a paracrine fashion to regulate vascular tone. Recent studies have demonstrated that endothelin-1 (ET-1) not only is produced by endothelial cells, but is also present in non-endothelial cells of atherosclerotic lesions. The present study was therefore designed to characterize the cell type and distribution of ET-expressing cells in different areas of human atherosclerotic coronary plaques, obtained by directional atherectomy of 30 patients. In addition, ET-1 messenger RNA (mRNA) distribution was studied in human atherosclerotic plaque tissue by in situ hybridization (ISH). The strongest ET-1-like immunoreactivity (ET-1-IR) was present in all cell-rich areas of 27 plaques. In fibrotic areas of 27 tissue samples, ET-1-IR was found in 44 per cent (12/27). ET expression was most prevalent in foamy macrophages (MPs, HAM 56-positive) and myofibroblasts (MFBs, alpha-actin-positive) in the vicinity of necrotic areas with signs of previous intraplaque haemorrhage. By contrast, ET-1-IR was weak and inconsistently found in MPs (11/27; 40 per cent) and MFBs (12/27; 44 per cent) in fibrous areas. Luminal endothelial cells (Ulex europeus agglutinin reaction-positive, UEA) exhibited strong ET-1-IR, whereas endothelial cells of intraplaque microvessels demonstrated inconsistent staining for ET-1. ISH revealed that ET mRNA is produced locally in intimal MPs showing strong ET-1-IR. These findings demonstrate that ET-1 is produced by human MPs, the principal inflammatory cell type in atherosclerosis, suggesting a role for ET-1 in the chronic inflammation associated with complicated atherosclerosis.
内皮素（ET）是一种非常强效的血管收缩肽，最初报道它由内皮细胞产生，并以旁分泌方式在局部起作用以调节血管张力。最近的研究表明，内皮素-1（ET-1）不仅由内皮细胞产生，还存在于动脉粥样硬化病变的非内皮细胞中。因此，本研究旨在通过对30例患者进行定向旋切术获取的人类动脉粥样硬化冠状动脉斑块不同区域中，鉴定表达ET的细胞类型和分布。此外，通过原位杂交（ISH）研究了人类动脉粥样硬化斑块组织中ET-1信使核糖核酸（mRNA）的分布。在27个斑块的所有富含细胞区域均存在最强的ET-1样免疫反应性（ET-1-IR）。在27个组织样本的纤维化区域中，44%（12/27）发现有ET-1-IR。在有斑块内出血迹象的坏死区域附近，ET表达在泡沫巨噬细胞（MPs，HAM 56阳性）和成肌纤维细胞（MFBs，α-肌动蛋白阳性）中最为普遍。相比之下，在纤维区域的MPs（11/27；40%）和MFBs（12/27；44%）中，ET-1-IR较弱且分布不一致。管腔内皮细胞（欧洲荆豆凝集素反应阳性，UEA）表现出强烈的ET-1-IR，而斑块内微血管的内皮细胞对ET-1的染色不一致。ISH显示，ET mRNA在显示强烈ET-1-IR的内膜MPs中局部产生。这些发现表明，ET-1由人类MPs产生，MPs是动脉粥样硬化中的主要炎症细胞类型，提示ET-1在与复杂动脉粥样硬化相关的慢性炎症中起作用。
