Oxidative stress increases internal calcium stores and reduces a key mitochondrial enzyme
Oxidative stress increases internal calcium stores and reduces a key mitochondrial enzyme
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DOI：
10.1016/s0925-4439(01)00091-6
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发表时间：
2002-03-16
影响因子：
6.2
通讯作者：
Jeitner, TM
中科院分区：
文献类型：
--
作者：
Gibson, GE;Zhang, H;Jeitner, TM
遗传性和非遗传性阿尔茨海默病 (AD) 患者的成纤维细胞表现出许多异常，包括铃蟾肽可释放钙储备 (BRCS) 增加、线粒体 α-酮戊二酸脱氢酶复合物 (KGDHC) 活性降低以及处理氧化应激的能力改变。基因突变（以及非基因形式的未知主要事件）与这些其他细胞异常之间的联系尚不清楚。为了确定氧化应激是否可能是产生其他 AD 相关变化的汇聚点，这些实验在成纤维细胞中测试了 H2O2（在存在或不存在选定抗氧化剂的情况下）对 BRCS 和 KGDHC 的影响。升高羧基二氯荧光素 (c-H2DCF) 可检测 ROS 的 H2O2 浓度会增加 BRCS 并降低 KGDHC 活性。这些变化与 AD 患者成纤维细胞的变化方向相同。使用抗氧化剂 Trolox 或 DMSO 进行急性处理，可将 c-H2DCF 可检测到的 ROS 降低约 90%，但会使 H2O2 诱导的 BRCS 增加约 4 倍，并且不会改变 KGDHC 的减少。 Trolox 的长期预处理使 BRCS 增加了一倍多，KGDHC 活性增加了三倍，并减少了 H2O2 的影响，用 DMSO 或 N-乙酰半胱氨酸预处理减少了 BRCS，但要么没有影响，要么夸大了 H2O2 引起的这些变量的变化。结果表明，BRCS 和 KGDHC 对 H2O2 衍生物质比 c-H2DCF 更敏感，并且抗氧化剂的氧化衍生物增强了 H2O2 的作用。这些发现支持这样的假设：氧化过程的选择性异常是导致 AD 患者细胞异常的级联反应的关键部分。 (C) 2001 Elsevier Science B.V. 保留所有权利。
Fibroblasts from patients with genetic and non-genetic forms of Alzheimer's disease (AD) show many abnormalities including increased bombesin-releasable calcium stores (BRCS), diminished activities of the mitochondrial alpha-ketoglutarate dehydrogenase complex (KGDHC), and an altered ability to handle oxidative stress. The link between genetic mutations (and the unknown primary event in non-genetic forms) and these other cellular abnormalities is unknown. To determine whether oxidative stress could be a convergence point that produces the other AD-related changes, these experiments tested in fibroblasts the effects of H2O2, in the presence or absence of select antioxidants, on BRCS and KGDHC. H2O2 concentrations that elevated carboxy-dichlorofluorescein (c-H2DCF)-detectable ROS increased BRCS and decreased KGDHC activity. These changes are in the same direction as those in fibroblasts from AD patients. Acute treatments with the antioxidants Trolox, or DMSO decreased c-H2DCF-detectable ROS by about 90%, but exaggerated the H2O2-induced increases in BRCS by about 4-fold and did not alter the reduction in KGDHC. Chronic pretreatments with Trolox more than doubled the BRCS, tripled KGDHC activities, and reduced the effects of H2O2, Pretreatment with DMSO or N-acetyl cysteine diminished the BRCS and either had no effect, or exaggerated the H2O2-induced changes in these variables. The results demonstrate that BRCS and KGDHC are more sensitive to H2O2 derived species than c-H2DCF, and that oxidized derivatives of the antioxidants exaggerate the actions of H2O2. The findings support the hypothesis that select abnormalities in oxidative processes are a critical part of a cascade that leads to the cellular abnormalities in cells from AD patients. (C) 2001 Elsevier Science B.V. All rights reserved.