4-hydroxynonenal induces mitochondrial oxidative stress, apoptosis and expression of glutathione S-transferase A4-4 and cytochrorne P450 2E1 in PC12 cells
4-hydroxynonenal induces mitochondrial oxidative stress, apoptosis and expression of glutathione S-transferase A4-4 and cytochrorne P450 2E1 in PC12 cells
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DOI：
10.1016/j.taap.2006.06.001
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发表时间：
2006-10-15
影响因子：
3.8
通讯作者：
John, Annie
中科院分区：
文献类型：
--
作者：
Raza, Haider;John, Annie
活性氧(ROS)的产生和氧化应激的过度和持续增加与许多疾病的发病机制有关。在本研究中，我们证明了脂质过氧化产物4-羟基壬烯醛(4-HNE)改变了培养的PC12细胞的谷胱甘肽(GSH)池并诱导氧化应激。这种增加伴随着亚细胞ROS和谷胱甘肽(GSH)代谢的变化。4-HNE处理后，线粒体和线粒体外的谷胱甘肽含量、谷胱甘肽过氧化物酶和谷胱甘肽还原酶活性均受到抑制，谷胱甘肽S转移酶活性升高，影响了谷胱甘肽的动态平衡。线粒体和线粒体上清液中细胞色素P450 2E1(CYP 2E1)的活性也随浓度和时间的增加而增加。4-HNE诱导的氧化应激还导致线粒体GSTA4-4、CYP2E1和Hsp70蛋白表达增加。PC12细胞氧化应激增加引起细胞凋亡，表现为线粒体细胞色素c释放、多聚(ADP-核糖)聚合酶(PARP)激活、DNA片段化和抗凋亡蛋白Bcl2表达减少。线粒体的呼吸和氧化还原功能似乎也受到4-HNE处理的显著影响。这些结果表明，HNE诱导的氧化应激和细胞凋亡可能与线粒体功能改变、GSH代谢和ROS清除受损有关。(C)2006 Elsevier Inc.保留所有权利。
An excessive and sustained increase in reactive oxygen species (ROS) production and oxidative stress have been implicated in the pathogenesis of many diseases. In the present study, we have demonstrated that 4-hydroxynonenal (4-HNE), a product of lipid peroxidation, alters glutathione (GSH) pools and induces oxidative stress in PC 12 cells in culture. This increase was accompanied by alterations in subcellular ROS and glutathione (GSH) metabolisms. The GSH homeostasis was affected as both mitochondrial and extramitochondrial GSH levels, GSH peroxidase and glutathione reductase activities were inhibited and glutathione S-transferase (GST) activity was increased after 4-HNE treatment. A concentration- and time-dependent increase in cytochrome P450 2E1 (CYP 2E1) activity in the mitochondria and postmitochondrial supernatant was also observed. 4-HNE-induced oxidative stress also caused an increase in the expression of GSTA4-4, CYP2E1 and Hsp70 proteins in the mitochondria. Increased oxidative stress in PC 12 cells initiated apoptosis as indicated by the release of mitochondrial cytochrome c, activation of poly-(ADP-ribose) polymerase (PARP), DNA fragmentation and decreased expression of antiapoptotic Bcl-2 proteins. Mitochondrial respiratory and redox functions also appeared to be affected markedly by 4-HNE treatment. These results suggest that HNE-induced oxidative stress and apoptosis might be associated with altered mitochondrial functions and a compromised GSH metabolism and ROS clearance. (c) 2006 Elsevier Inc. All rights reserved.