ABSTRACT Endothelin-1 (ET-1) induces contraction, proliferation, and collagen synthesis of activated hepatic stellate cells and is a potent mediator of portal hypertension. Endothelin-converting enzyme-1 (ECE-1) generates ET-1 from the inactive precursor big-endothelin-1. The cellular distribution and activity of ECE-1 in the liver is unknown. Hepatic fibrogenesis was induced in rats by CCl4 administration and secondary biliary cirrhosis after 6 weeks of complete bile duct occlusion (BDO). The tissue ET-1 and ET receptor protein levels were quantified, the ECE-1 isoform mRNAs were measured by RNase protection assay and ECE-1 activity was analyzed. ECE-1a and -b mRNA were upregulated in biliary cirrhosis and in CCl4-injured livers, whereas ECE-1c mRNA remained unchanged. ECE-1 activity was increased after BDO and peaked at 12 h after acute CCl4-intoxication. Tissue levels of ET-1, ETA- and ETB receptors were elevated 7-, 5-, and 4.6-fold in cirrhotic rats, respectively. ECE-1 activity increased following BDO and acute CCl4-intoxication. In conclusion, ECE-1a and -b RNAs are upregulated in fibrogenesis, indicating that these isoforms play a central role in ET-1 generation during fibrogenesis and portal hypertension.

中文翻译：

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内皮素转化酶1在急慢性肝纤维化损伤中的表达

摘要 Endothelin-1 (ET-1) 诱导活化肝星状细胞的收缩、增殖和胶原合成，并且是门静脉高压的有效介质。内皮素转化酶-1 (ECE-1) 从无活性的前体大内皮素-1 生成 ET-1。ECE-1 在肝脏中的细胞分布和活性尚不清楚。在完全胆管闭塞 (BDO) 6 周后，通过 CCl4 给药和继发性胆汁性肝硬化在大鼠中诱导肝纤维化。量化组织 ET-1 和 ET 受体蛋白水平，通过 RNase 保护测定测量 ECE-1 同种型 mRNA，并分析 ECE-1 活性。ECE-1a 和 -b mRNA 在胆汁性肝硬化和 CCl4 损伤的肝脏中上调，而 ECE-1c mRNA 保持不变。ECE-1 活性在 BDO 后增加，并在急性 CCl4 中毒后 12 小时达到峰值。ET-1、ETA 和 ETB 受体的组织水平在肝硬化大鼠中分别升高了 7、5 和 4.6 倍。BDO 和急性 CCl4 中毒后 ECE-1 活性增加。总之，ECE-1a 和 -b RNA 在纤维化过程中上调，表明这些同工型在纤维化和门静脉高压期间的 ET-1 生成中起核心作用。