Hepatitis C virus core protein inhibits deoxycholic acid-mediated apoptosis despite generating mitochondrial reactive oxygen species
Hepatitis C virus core protein inhibits deoxycholic acid-mediated apoptosis despite generating mitochondrial reactive oxygen species
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DOI：
10.1007/s00535-005-1738-1
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发表时间：
2006-03-01
影响因子：
6.3
通讯作者：
Okita, K
中科院分区：
文献类型：
--
作者：
Hara, Y;Hino, K;Okita, K
背景资料。丙型肝炎病毒(丙型肝炎病毒)核心蛋白可引起氧化应激并改变细胞凋亡途径。然而，细胞凋亡的结果并不一致，氧化应激的真正意义还不是很清楚。这项研究的目的有两个。首先，我们想要确认核心诱导的氧化应激是否真的足够严重，足以导致DNA损伤，以及它是否诱导了细胞抗氧化反应。其次，我们想要评估这种核心诱导的氧化应激和对其的抗氧化反应是否与细胞凋亡的变化有关。方法：研究方法。在Huh-7细胞和HeLa细胞中，丙型肝炎病毒核心蛋白在Tet-off启动子的控制下表达。我们选择使用脱氧胆酸(DCA)作为模型，因为已知它同时产生活性氧物种(ROS)和细胞凋亡。结果。在基础和DCA刺激条件下，核心蛋白的表达均增加ROS和8-羟基-2‘-脱氧鸟苷(8-OHdG)。核心蛋白的表达也增加了锰超氧化物歧化酶的水平。核心蛋白抑制DCA介导的线粒体膜去极化和DCA介导的caspase-9和caspase-3的激活，而DCA增加ROS。核心蛋白通过增加Bclx(L)蛋白，减少Bax蛋白，而不影响Bax蛋白在线粒体和胞浆中的比例，从而抑制细胞色素c从线粒体释放到细胞质，从而抑制DCA介导的细胞凋亡。结论。丙型肝炎病毒核心蛋白诱导DNA氧化损伤，同时抑制细胞凋亡，同时促进ROS的产生。因此，氧化应激和核心蛋白对细胞凋亡的调控是相互独立的。
Background. Hepatitis C virus (HCV) core protein is known to cause oxidative stress and alter apoptosis pathways. However, the apoptosis results are inconsistent, and the real significance of oxidative stress is not well known. The aim of this study was twofold. First, we wanted to confirm whether core-induced oxidative stress was really significant enough to cause DNA damage, and whether it induced cellular antioxidant responses. Second, we wanted to evaluate whether this core-induced oxidative stress and the antioxidant response to it was responsible for apoptosis changes. Methods. HCV core protein was expressed Under control of the Tet-Off promoter in Huh-7 cells and HeLa cells. We chose to use deoxycholic acid (DCA) as a model because it is known to produce both reactive oxygen species (ROS) and apoptosis. Results. Core expression uniformly increased ROS and 8-hydroxy-2'-deoxyguanosine (8-OHdG) under basal and DCA-stimulated conditions. Core protein expression also increased manganese superoxide dismutase levels. Core protein inhibited DCA-mediated mitochondrial membrane depolarization and DCA-mediated activation of caspase-9 and caspase-3, despite the increase in ROS by DCA. Core protein inhibited DCA-mediated apoptosis by increasing Bcl-x(L) protein and decreasing Bax protein, without affecting the proportion of Bax between mitochondria and cytosol, resulting in suppression of cytochrome c release from mitochondria into cytoplasm. Conclusions. HCV core protein induces oxidative DNA damage, whereas it inhibits apoptosis that is accompanied by enhancement of ROS production. Thus, oxidative stress and apoptosis modulation by core protein are independent of each other.