Wang Yang Q, Luk John M, Ikeda Kazuo, Man Kwan, Chu Andrew C, Kaneda Kenji, Fan Sheung Tat
Centre for the Study of Liver Disease and Department of Surgery, The University of Hong Kong, Pokfulam, Hong Kong.
Biochem Biophys Res Commun. 2004 Apr 30;317(2):358-62. doi: 10.1016/j.bbrc.2004.03.050.
Activated hepatic stellate cells (HSCs) produce cyclooxygenase-2 (COX-2) protein to induce vascular endothelial growth factor (VEGF) production that participates in angiogenesis in injured liver. To reveal the unknown regulatory mechanism, we used hypoxic atmosphere mimicking injured-tissue microenvironment to induce VEGF expression in a rat hepatic stellate cell line (T6-HSCs). The present study showed that hypoxia up-regulated the protein levels of COX-2 and hypoxia-inducible factor-1-alpha (HIF-1alpha), but rapidly effected degradation of von Hippel-Lindau (vHL) protein. As a result, expression of VEGF in HSCs was markedly elevated; and pretreatment with COX-2 inhibitors (nimesulide or indomethacin) could significantly ameliorate the angiogenic event. Collectively, hypoxic HSCs increased accumulation of HIF-1alpha protein and induced VEGF expression in a time-dependent manner. Inhibition of COX-2 activities would prevent vHL protein from degradation and suppress HIF-1alpha up-regulation. Thus, vHL/HIF-1alpha has a regulatory role in COX-2-mediated VEGF production in hypoxic stellate cells in injured liver.
活化的肝星状细胞（HSCs）产生环氧合酶-2（COX-2）蛋白，以诱导血管内皮生长因子（VEGF）的产生，而VEGF参与受损肝脏的血管生成。为了揭示未知的调控机制，我们使用模拟受损组织微环境的低氧环境来诱导大鼠肝星状细胞系（T6-HSCs）中VEGF的表达。本研究表明，低氧上调了COX-2和缺氧诱导因子-1α（HIF-1α）的蛋白水平，但迅速导致了冯·希佩尔-林道（vHL）蛋白的降解。结果，肝星状细胞中VEGF的表达显著升高；用COX-2抑制剂（尼美舒利或吲哚美辛）预处理可显著改善血管生成事件。总体而言，低氧肝星状细胞以时间依赖性方式增加HIF-1α蛋白的积累并诱导VEGF表达。抑制COX-2活性可防止vHL蛋白降解并抑制HIF-1α上调。因此，vHL/HIF-1α在受损肝脏低氧星状细胞中COX-2介导的VEGF产生中具有调控作用。
