Protection against Fas-induced liver apoptosis in transgenic mice expressing cyclooxygenase 2 in hepatocytes
Protection against Fas-induced liver apoptosis in transgenic mice expressing cyclooxygenase 2 in hepatocytes
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DOI：
10.1002/hep.21556
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发表时间：
2007-03-01
期刊：
影响因子：
13.5
通讯作者：
Martin-Sanz, Paloma
中科院分区：
文献类型：
--
作者：
Casado, Marta;Molla, Belen;Martin-Sanz, Paloma
环氧合酶-2（考克斯-2）在许多癌症中上调，并且合成的前列腺素类在若干组织中增加增殖、改善血管生成并抑制细胞凋亡。为了研究考克斯-2在肝脏中的功能，产生了含有由人ApoE启动子控制的人考克斯-2 cDNA组成的融合基因（LIVh考克斯-2）的转基因（Tg）小鼠。开发了6个细胞系;它们都在肝细胞中选择性表达LIVhCOX-2转基因。Tg小鼠表现出正常的表型，发现PGE（2）水平升高是由于组成型表达的考克斯-2。不同组织的组织学分析和肝脏的肉眼检查显示野生型（Wt）和Tg动物之间无差异。然而，Tg动物抵抗Fas介导的肝损伤，表现为血浆转氨酶水平低，caspase-3活化较少，Bax水平和Bcl-2，Mcl-1，和xIAP蛋白的增加，与野生型动物相比。此外，在存在考克斯-2选择性抑制剂的情况下，对Fas介导的细胞凋亡的抗性被抑制，这阻止了前列腺素在Tg小鼠肝脏中的积累。结论：考克斯-2依赖的野牡丹素表达对肝细胞凋亡具有保护作用。
Cyclooxygenase-2 (COX-2) is upregulated in many cancers, and the prostanoids synthesized increase proliferation, improve angiogenesis, and inhibit apoptosis in several tissues. To explore the function of COX-2 in liver, transgenic (Tg) mice were generated containing a fusion gene (LIVhCOX-2) consisting of human COX-2 cDNA under the control of the human ApoE promoter. Six lines were developed; all of them expressed the LIVhCOX-2 transgene selectively in hepatocytes. The Tg mice exhibited a normal phenotype, and the increased levels of PGE(2) found were due to the constitutively expressed COX-2. Histological analysis of different tissues and macroscopic examination of the liver showed no differences between wild-type (Wt) and Tg animals. However, Tg animals were resistant to Fas-mediated liver injury, as demonstrated by low levels of plasmatic aminotransferases, a lesser caspase-3 activation, and Bax levels and an increase in Bcl-2, Mcl-1, and xIAP proteins, when compared with the Wt animals. Moreover, the resistance to Fas-mediated apoptosis is suppressed in the presence of COX-2-selective inhibitors, which prevented prostaglandin accumulation in the liver of Tg mice. Conclusion: These results demonstrate that expression of COX-2-dependent prostaglandins exerted a protection against liver apoptosis.