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人低密度脂蛋白及血浆在暴露于3-吗啉代非那烯和试剂过氧亚硝酸盐时的氧化与抗氧化作用

Oxidation and antioxidation of human low-density lipoprotein and plasma exposed to 3-morpholinosydnonimine and reagent peroxynitrite.

作者信息

Thomas S R, Davies M J, Stocker R

机构信息

The Biochemistry and EPR Groups, The Heart Research Institute, 145 Missenden Road, Camperdown, Sydney, NSW 2050, Australia.

出版信息

Chem Res Toxicol. 1998 May;11(5):484-94. doi: 10.1021/tx970173a.

Abstract

As peroxynitrite is implicated as an oxidant for low-density lipoprotein (LDL) in atherogenesis, we investigated this process using reagent peroxynitrite (ONOO-) and 3-morpholinosydnonimine (SIN-1, which produces peroxynitrite via generation of NO. and O2.-). LDL oxidation was assessed by the consumption of ubiquinol-10 (CoQ10H2) and alpha-tocopherol (alpha-TOH), the accumulation of cholesteryl ester hydro(pero)xides, the loss of lysine (Lys) and tryptophan (Trp) residues, and the change in relative electrophoretic mobility. Exposure to ONOO- or SIN-1 resulted in rapid (<1 min) and time-dependent oxidation, respectively, of LDL's lipids and protein. Manipulating the alpha-TOH content by in vivo or in vitro means showed that when ONOO- or SIN-1 was used at oxidant-to-LDL ratios of <100:1 the extent of LDL lipid peroxidation increased with increasing initial alpha-TOH content. In contrast, in vivo enrichment with the co-antioxidant CoQ10H2 decreased LDL lipid peroxidation induced by SIN-1. At oxidant-to-LDL ratios of >200:1, alpha-TOH enrichment decreased LDL lipid peroxidation for both SIN-1 and ONOO-. In contrast to lipid peroxidation, altering the alpha-TOH content of LDL did not affect Trp or Lys loss, independent of the amounts of either oxidant added. Aqueous antioxidants inhibited ONOO--induced lipid and protein oxidation with the order of efficacy: 3-hydroxyanthranilate (3-HAA) > urate > ascorbate. With SIN-1, these antioxidants inhibited Trp consumption, while only the co-antioxidants ascorbate and 3-HAA prevented alpha-TOH consumption and lipid peroxidation. Exposure of human plasma to SIN-1 resulted in the loss of ascorbate followed by loss of CoQ10H2 and bilirubin. Lipid peroxidation was inhibited during this period, though proceeded as a radical-chain process after depletion of these antioxidants and in the presence of alpha-TOH and urate. Bicarbonate at physiological concentrations decreased ONOO--induced lipid and protein oxidation, whereas it enhanced SIN-1-induced lipid peroxidation, Trp consumption, and alpha-tocopheroxyl radical formation in LDL. These results indicate an important role for tocopherol-mediated peroxidation and co-antioxidation in peroxynitrite-induced lipoprotein lipid peroxidation, especially when peroxynitrite is formed time-dependently by SIN-1. The studies also highlight differences between ONOO-- and SIN-1-induced LDL oxidation with regards to the effects of bicarbonate, ascorbate, and urate.

摘要

由于过氧亚硝酸盐被认为是动脉粥样硬化中低密度脂蛋白(LDL)的氧化剂,我们使用试剂过氧亚硝酸盐(ONOO-)和3-吗啉代辛二酰亚胺(SIN-1,其通过生成NO和O2-产生过氧亚硝酸盐)来研究这一过程。通过泛醇-10(CoQ10H2)和α-生育酚(α-TOH)的消耗、胆固醇酯氢(过)氧化物的积累、赖氨酸(Lys)和色氨酸(Trp)残基的损失以及相对电泳迁移率的变化来评估LDL氧化。暴露于ONOO-或SIN-1分别导致LDL的脂质和蛋白质快速(<1分钟)且随时间变化的氧化。通过体内或体外方法操纵α-TOH含量表明,当以<100:1的氧化剂与LDL比例使用ONOO-或SIN-1时,LDL脂质过氧化程度随初始α-TOH含量的增加而增加。相反,体内用抗氧化剂CoQ10H2富集可降低SIN-1诱导的LDL脂质过氧化。在氧化剂与LDL比例>200:1时,α-TOH富集降低了SIN-1和ONOO-诱导的LDL脂质过氧化。与脂质过氧化相反,改变LDL的α-TOH含量不影响Trp或Lys的损失,与添加的任何一种氧化剂的量无关。水性抗氧化剂抑制ONOO-诱导的脂质和蛋白质氧化,其功效顺序为:3-羟基邻氨基苯甲酸(3-HAA)>尿酸盐>抗坏血酸盐。对于SIN-1,这些抗氧化剂抑制Trp消耗,而只有抗氧化剂抗坏血酸盐和3-HAA可防止α-TOH消耗和脂质过氧化。人血浆暴露于SIN-1导致抗坏血酸盐损失,随后是CoQ10H2和胆红素损失。在此期间脂质过氧化受到抑制,尽管在这些抗氧化剂耗尽后且在存在α-TOH和尿酸盐的情况下作为自由基链过程继续进行。生理浓度的碳酸氢盐降低ONOO-诱导的脂质和蛋白质氧化,而它增强SIN-1诱导的LDL脂质过氧化、Trp消耗和α-生育酚自由基形成。这些结果表明生育酚介导的过氧化和抗氧化在过氧亚硝酸盐诱导的脂蛋白脂质过氧化中起重要作用,特别是当过氧亚硝酸盐由SIN-1随时间形成时。这些研究还突出了在碳酸氢盐、抗坏血酸盐和尿酸盐的影响方面ONOO-和SIN-1诱导的LDL氧化之间的差异。

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