Attenuation of hemolysate-induced cerebrovascular endothelial cell injury and of production of endothelin-1 and big endothelin-1 by an endothelin-converting enzyme inhibitor
Attenuation of hemolysate-induced cerebrovascular endothelial cell injury and of production of endothelin-1 and big endothelin-1 by an endothelin-converting enzyme inhibitor
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DOI：
10.1016/s0090-3019(02)00824-8
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发表时间：
2002-09-01
影响因子：
--
通讯作者：
Lee, KS
中科院分区：
文献类型：
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作者：
Chang, CZ;Winardi, D;Lee, KS
内皮素-1 （ET-1）是一种有效的长效血管收缩肽，与蛛网膜下腔出血（SAH）后脑血管痉挛的发病机制有关。ET-1已被证明存在于SAH后患者的脑脊液中，而蛛网膜下腔血块溶血过程中产生的物质被认为是刺激ET-1产生的原因。et - 1的生物合成是一个多步骤的过程，包括相对不活跃的前体大et - 1通过内皮素转换酶（ECE），一种金属蛋白酶转化为成熟的肽。因此，ECE抑制剂有望抑制et - 1的生物合成，并减少这种肽过量产生的病理影响。本研究的目的是研究ECE抑制剂CGS 26303对溶血诱导的脑血管内皮细胞损伤的影响，以及这些细胞产生ET-1的影响。方法在培养液中加入不同剂量的CGS 26303和溶血液，培养48小时。通过细胞形态和密度评估细胞损伤，通过放射免疫测定ET-1和大ET-1的产生。结果单独溶血液使培养液中ET-1和大ET-1水平升高，造成大量细胞损失。CGS 26303抑制溶血引起的ET-1和大ET-1水平升高，减少内皮细胞损伤。当CGS 26303与溶血液同时加入时，其保护作用不明显，但当CGS 26303在加入溶血液前30分钟给予时，其保护作用显著且呈剂量依赖性。结论ET-1的过量产生在溶血剂诱导的脑血管内皮细胞损伤中起重要作用。(C) 2002年由爱思唯尔科学公司
BACKGROUND Endothelin-1 (ET-1) is a potent and long-acting vasoconstrictive peptide that has been implicated in the pathogenesis of cerebral vasospasm after subarachnoid hemorrhage (SAH). ET-1 has been shown to be present in the cerebrospinal fluid of patients after SAH, and substances produced during hemolysis of subarachnoid blood clots are believed to be responsible for stimulating the production of ET-1. The biosynthesis of ET-I is a multi-step process, involving the conversion of the relatively inactive precursor big ET-I to the mature peptide by endothelin converting enzyme (ECE), a metalloprotease. Consequently, ECE inhibitors are expected to suppress the biosynthesis of ET-I and reduce the pathologic impact resulting from overproduction of this peptide. The purpose of the present study was to investigate the effects of an ECE inhibitor, CGS 26303, on hemolysate-induced injury of cerebral vessel endothelial cells as well as the production of ET-1 from these cells.METHODS Different doses of CGS 26303 and hemolysate were added to the culture medium for 48 hours. Cell injury was assessed by cell morphology and density, while the productions of ET-1 and big ET-1 were determined by radioimmunoassays.RESULTS Hemolysate alone increased the levels of ET-1 and big ET-I in culture medium and caused substantial cell loss. Treatment with CGS 26303 inhibited the hemolysate-induced increases in the levels of ET-I and big ET-1 and reduced endothelial cell injury. The protective effects of CGS 26303 were modest when this inhibitor was added simultaneously with hemolysate, but were prominent and dose-dependent when the inhibitor was given 30 minutes before the addition of hemolysate.CONCLUSION These results suggest that overproduction of ET-1 contributes significantly to hemolysate-induced damage to cerebrovascular endothelial cells. (C) 2002 by Elsevier Science Inc.