Proteasome inhibition in oxidative stress neurotoxicity: implications for heat shock proteins
Proteasome inhibition in oxidative stress neurotoxicity: implications for heat shock proteins
复制标题
DOI：
10.1046/j.1471-4159.2001.00302.x
复制
发表时间：
2001-05-01
影响因子：
4.7
通讯作者：
Keller, JN
中科院分区：
文献类型：
--
作者：
Ding, QX;Keller, JN
最近的研究表明，蛋白酶体（一种负责大部分细胞内蛋白质水解的酶）的抑制可能与氧化应激相关的毒性有关。在本研究中，我们证明暴露于氧化损伤(百草枯，H2O2。FeSO4)诱导SH-SY5Y神经细胞活性氧（ROS）快速增加，线粒体膜电位丧失，蛋白酶体活性抑制，诱导细胞死亡。应用蛋白酶体抑制剂（MG115、环氧霉素）模拟氧化应激源对线粒体膜电位和细胞活力的影响，并增加对氧化损伤的易感性。稳定转染人HDJ-1（热休克蛋白家族成员）的神经SH-SY5Y细胞对氧化应激相关的细胞毒性更具抗性。表达HDJ-1水平升高的细胞在氧化应激后表现出类似程度的ROS形成，但在氧化损伤后表现出更大程度的线粒体功能和蛋白酶体活性保存。转染HDJ-1的细胞也更能抵抗与蛋白酶体抑制剂应用相关的毒性。这些数据支持了蛋白酶体抑制在氧化应激毒性中的可能作用，并提示热休克蛋白可能通过保持蛋白酶体功能和减弱蛋白酶体抑制的毒性来赋予氧化应激抗性。
Recent studies have demonstrated that inhibition of the proteasome, an enzyme responsible for the majority of intracellular proteolysis, may contribute to the toxicity associated with oxidative stress. In the present study we demonstrate that exposure to oxidative injury (paraquat, H2O2. FeSO4) induces a rapid increase in reactive oxygen species (ROS), loss of mitochondrial membrane potential, inhibition of proteasome activity, and induction of cell death in neural SH-SY5Y cells. Application of proteasome inhibitors (MG115, epoxomycin) mimicked the effects of oxidative stressors on mitochondrial membrane potential and cell viability, and increased vulnerability to oxidative injury. Neural SH-SY5Y cells stably transfected with human HDJ-1, a member of the heat shock protein family, were more resistant to the cytotoxicity associated with oxidative stressors. Cells expressing increased levels of HDJ-1 displayed similar degrees of ROS formation following oxidative stressors, but demonstrated a greater preservation of mitochondrial function and proteasomal activity following oxidative injury. Cells transfected with HDJ-1 were also more resistant to the toxicity associated with proteasome inhibitor application. These data support a possible role for proteasome inhibition in the toxicity of oxidative stress, and suggest heat shock proteins may confer resistance to oxidative stress, by preserving proteasome function and attenuating the toxicity of proteasome inhibition.