Patterson Rebecca A, Horsley Elizabeth T M, Leake David S
Cell and Molecular Biology Research Division, School of Animal and Microbial Sciences, The University of Reading, Whiteknights, PO Box 228, Reading, Berkshire, RG6 6AJ, United Kingdom.
J Lipid Res. 2003 Mar;44(3):512-21. doi: 10.1194/jlr.M200407-JLR200. Epub 2002 Dec 16.
Oxidized LDL is present within atherosclerotic lesions, demonstrating a failure of antioxidant protection. A normal human serum ultrafiltrate of Mr below 500 was prepared as a model for the low Mr components of interstitial fluid, and its effects on LDL oxidation were investigated. The ultrafiltrate (0.3%, v/v) was a potent antioxidant for native LDL, but was a strong prooxidant for mildly oxidized LDL when copper, but not a water-soluble azo initiator, was used to oxidize LDL. Adding a lipid hydroperoxide to native LDL induced the antioxidant to prooxidant switch of the ultrafiltrate. Uric acid was identified, using uricase and add-back experiments, as both the major antioxidant and prooxidant within the ultrafiltrate for LDL. The ultrafiltrate or uric acid rapidly reduced Cu2+ to Cu+. The reduction of Cu2+ to Cu+ may help to explain both the antioxidant and prooxidant effects observed. The decreased concentration of Cu2+ would inhibit tocopherol-mediated peroxidation in native LDL, and the generation of Cu+ would promote the rapid breakdown of lipid hydroperoxides in mildly oxidized LDL into lipid radicals. The net effect of the low Mr serum components would therefore depend on the preexisting levels of lipid hydroperoxides in LDL. These findings may help to explain why LDL oxidation occurs in atherosclerotic lesions in the presence of compounds that are usually considered to be antioxidants.
氧化型低密度脂蛋白（Oxidized LDL）存在于动脉粥样硬化病变中，这表明抗氧化保护机制失效。制备了分子量低于500的正常人血清超滤物，作为组织间液低分子量成分的模型，并研究了其对低密度脂蛋白氧化的影响。该超滤物（0.3%，v/v）对天然低密度脂蛋白是一种有效的抗氧化剂，但当用铜（而非水溶性偶氮引发剂）氧化低密度脂蛋白时，它对轻度氧化的低密度脂蛋白却是一种强促氧化剂。向天然低密度脂蛋白中添加脂质氢过氧化物会诱导超滤物从抗氧化剂转变为促氧化剂。通过尿酸酶和回补实验确定，尿酸是超滤物中对低密度脂蛋白起主要抗氧化和促氧化作用的物质。超滤物或尿酸能迅速将Cu2+还原为Cu+。Cu2+还原为Cu+可能有助于解释所观察到的抗氧化和促氧化作用。Cu2+浓度降低会抑制天然低密度脂蛋白中生育酚介导的过氧化反应，而Cu+的生成会促进轻度氧化的低密度脂蛋白中的脂质氢过氧化物迅速分解为脂质自由基。因此，低分子量血清成分的净效应将取决于低密度脂蛋白中脂质氢过氧化物的预先存在水平。这些发现可能有助于解释为什么在通常被认为是抗氧化剂的化合物存在的情况下，低密度脂蛋白氧化仍会在动脉粥样硬化病变中发生。
