Chronic depletion of glutathione (GSH) and minimal modification of LDL in vivo: its prevention by glutathione mono ester (GME) therapy
Chronic depletion of glutathione (GSH) and minimal modification of LDL in vivo: its prevention by glutathione mono ester (GME) therapy
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DOI：
10.1016/j.bbadis.2004.11.025
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发表时间：
2005-06-30
影响因子：
6.2
通讯作者：
Devaraj, H
中科院分区：
文献类型：
--
作者：
Rajasekaran, NS;Sathyanarayanan, S;Devaraj, H
还原型谷胱甘肽（GSH）水平的下降与衰老和自由基介导的疾病有关。本研究的目的是确定细胞外GSH的慢性消耗是否会对循环大分子（如脂蛋白）造成氧化损伤。用一种选择性谷胱甘肽抑制剂丁硫丙磺酰亚胺（BSO）处理的大鼠，血浆谷胱甘肽、维生素E和抗坏血酸浓度降低。BSO处理组LDL中丙二醛（MDA）和共轭二烯含量显著升高（P < 0.01），维生素E含量显著降低（P < 0.01）。总胆固醇和低密度脂蛋白胆固醇的分析显示，对照组和实验组之间的显着变化。感兴趣的是，从BSO介导的最低限度修饰的LDL中记录了溶血磷脂酰胆碱（Lyso-PC）和磷脂酰胆碱（PC）的浓度变化。LDL-BDC/MDA与其抗氧化能力呈负相关。经CuSO 4体外氧化后，纯化的LDL-载脂蛋白-B在琼脂糖凝胶上的电泳行为显示，在BSO处理的大鼠中，迁移率增加，表明LDL的体内修饰变得对体外氧化敏感。从BSO处理的动物中分离的LDL（体外氧化后）的迁移率增加与其氨基减少相关，如通过三硝基苯磺酸（TNBS）反应物测定的。然而，LDL分子的流动性没有改变，由于BSO处理在体内。有趣的是，对LDL的最小修饰不会导致注射BSO的大鼠背主动脉中的任何血管损伤。对用L-丁硫氨酸-SR-亚砜亚胺（BSO，4 mmol/kg体重，每天两次，持续30天）处理的动物以5 mmol/kg体重的剂量施用谷胱甘肽单酯（GME），持续30天，使抗氧化剂状态正常化并防止对LDL的最小修饰。因此，增加细胞GSH水平可触发对抗氧化应激的有益作用。(c)2004 Elsevier B. V.保留所有权利。
A decline in reduced glutathione (GSH) level is associated with aging and free radical mediated diseases. The objective of this study was to determine whether the chronic depletion of extra cellular GSH causes oxidative damage to the circulating macromolecules such as lipoproteins. Decreased concentrations of plasma glutathione, vitamin E and ascorbic acid were recorded in the rats treated with buthionine sulfoximine (BSO), a selective GSH inhibitor. In LDL isolated from BSO-treated animals, the concentration of malondialdehyde (MDA) and conjugated dienes were significantly increased (P < 0.01), whereas the levels of vitamin E were decreased (P < 0.01). The analysis of total and LDL cholesterol revealed significant changes between the control and experimental groups. Of interest, altered concentrations of lysophosphatidyl choline (Lyso-PC) and phosphatidyl choline (PC) were recorded from the BSO mediated minimally modified LDL. A negative correlation between LDL-BDC/MDA and its antioxidant capacity was noted. Upon in vitro oxidation with CuSO4, the electrophoretic behavior of purified LDL-apoprotein-B on agarose gel showed an increased mobility in BSO-treated rats, indicative of in vivo modification of LDL to become susceptible for in vitro oxidation. The increased mobility of LDL (after in vitro oxidation) isolated from the BSO-treated animals correlates with a decrease in its amino groups, as determined by the trinitrobenzene sulfonic acid (TNBS) reactants. However, the mobility of LDL molecule was not altered due to BSO treatment in vivo. Interestingly, the minimal modification on LDL does not lead to any vascular damage in the dorsal aorta of the rats injected with BSO. The administration of glutathione monoester (GME), at a dose of 5 mmol/kg body weight, twice a day, for 30 days, to animals treated with L-buthionine-SR-sulfoximine (BSO, 4 mmol/kg body weight, twice a day, for 30 days) normalized the antioxidant status and prevented the minimal modifications on LDL. Thus, increasing the cellular GSH levels may trigger beneficial effects against oxidative stress. (c) 2004 Elsevier B.V. All rights reserved.