Philis-Tsimikas A, Parthasarathy S, Picard S, Palinski W, Witztum J L
Department of Medicine, University of California San Diego, La Jolla 92093, USA.
Arterioscler Thromb Vasc Biol. 1995 Mar;15(3):367-76. doi: 10.1161/01.atv.15.3.367.
We previously demonstrated that aminoguanidine (AMGN) was able to prevent oxidative modification of LDL. Initially, we thought that this occurred solely because AMGN trapped reactive breakdown products of lipid peroxidation and prevented apoB modification, similar to AMGN's proposed ability to trap reactive glucose intermediates and prevent advanced glycosylation end-product formation. We now demonstrate that AMGN also displays dose-dependent pro-oxidant and antioxidant activity toward LDL. Moderate doses of AMGN (0.05 to 1.0 mmol/L) prevented lipid peroxidation in LDL exposed to copper. AMGN prevented the loss of polyunsaturated fatty acids and delayed or prevented conjugated-diene formation, both of which are sensitive indicators of lipid peroxidation. The same doses of AMGN also prevented apoB modification, a step distal to lipid peroxidation, as evidenced by the ability to (1) prevent fluorescence at 420 nm, (2) block enhanced electrophoretic mobility, and (3) prevent changes leading to enhanced macrophage uptake. Thus, AMGN inhibits LDL modification both by inhibiting lipid peroxidation as well as by trapping reactive breakdown products of lipid peroxidation. It was also demonstrated that for every LDL, there was also a very low dose of AMGN (about 0.01 mmol/L) that actually promoted lipid oxidation and subsequent protein modification. This activity of AMGN could be enhanced by increasing the content of lipid hydroperoxide in the LDL, eg, by aging or radioiodinating the LDL. Conversely, the pro-oxidant activity could be reduced by pretreatment of LDL with ebselen or vitamin E. We propose a mechanism by which AMGN effects pro-oxidant activity toward LDL at very low concentrations and antioxidant activity at higher concentrations and discuss the practical implications of these observations.
我们先前证明氨基胍（AMGN）能够防止低密度脂蛋白（LDL）的氧化修饰。起初，我们认为这仅仅是因为AMGN捕获了脂质过氧化的活性分解产物并防止载脂蛋白B（apoB）修饰，类似于AMGN所提出的捕获活性葡萄糖中间体并防止晚期糖基化终产物形成的能力。我们现在证明，AMGN对LDL还表现出剂量依赖性的促氧化和抗氧化活性。中等剂量的AMGN（0.05至1.0 mmol/L）可防止暴露于铜的LDL发生脂质过氧化。AMGN可防止多不饱和脂肪酸的损失，并延迟或防止共轭二烯的形成，这两者都是脂质过氧化的敏感指标。相同剂量的AMGN还可防止apoB修饰，这是脂质过氧化之后的一个步骤，证据如下：（1）防止420 nm处的荧光；（2）阻止电泳迁移率增强；（3）防止导致巨噬细胞摄取增强的变化。因此，AMGN通过抑制脂质过氧化以及捕获脂质过氧化的活性分解产物来抑制LDL修饰。还证明了对于每个LDL，也存在非常低剂量的AMGN（约0.01 mmol/L），实际上它会促进脂质氧化和随后的蛋白质修饰。通过增加LDL中脂质过氧化氢的含量，例如通过使LDL老化或进行放射性碘化，可以增强AMGN的这种活性。相反，用依布硒啉或维生素E预处理LDL可以降低其促氧化活性。我们提出了一种机制，通过该机制AMGN在非常低的浓度下对LDL发挥促氧化活性，在较高浓度下发挥抗氧化活性，并讨论了这些观察结果的实际意义。
