Correlation of antiphospholipid antibody recognition with the structure of synthetic oxidized phospholipids -: Importance of Schiff base formation and aldol condensation
Correlation of antiphospholipid antibody recognition with the structure of synthetic oxidized phospholipids -: Importance of Schiff base formation and aldol condensation
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DOI：
10.1074/jbc.m108860200
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发表时间：
2002-03-01
影响因子：
4.8
通讯作者：
Dennis, EA
中科院分区：
文献类型：
--
作者：
Friedman, P;Hörkkö, S;Dennis, EA
低密度脂蛋白（LDL）的氧化通过多种途径与动脉粥样硬化形成相关。该过程涉及非特异性断裂、氧化分解以及低密度脂蛋白的脂质和蛋白质的修饰。该方法产生了多种生物活性产物，包括含磷脂酰胆碱的磷脂，其可以与伯胺（即肽或磷脂头部基团）交叉反应以产生席夫碱产物。我们还表明，这种氧化磷脂产品可能会进一步通过氧化后的化学途径，涉及羟醛缩合反应。EO 6是氧化磷脂的IgM单克隆自身抗体，可阻断巨噬细胞对氧化LDL（OxLDL）的摄取。由于EO 6的表位也阻断OxLDL的摄取，因此已经合成和表征了一系列氧化磷脂、其肽复合物和其羟醛缩合物，并且已经测定了它们的抗原性。本研究定义了负责EO 6抗原性的氧化磷脂的结构基序。某些含有短链脂肪酸的单体磷脂无论在sn-2位氧化与否都具有抗原性。然而，含有sn-1长链脂肪酸的氧化磷脂不具有抗原性，除非sn-2氧化脂肪酸含有首先与肽反应产生席夫碱的醛，或者sn-2氧化脂肪酸经历羟醛型自缩合。我们的数据表明，磷酸胆碱头基是必不可少的抗原性，但其可用性取决于氧化磷脂构象。我们认为，氧化后，类似的反应发生在磷脂表面的低密度脂蛋白，产生巨噬细胞识别的配体。这种类型的氧化磷脂的合成亚胺加合物能够阻断OxLDL的摄取。
The oxidation of low density lipoproteins (LDL) has been correlated with atherogenesis through a variety of pathways. The process involves nonspecific fragmentation, oxidative breakdown, and modification of the lipids and protein of LDL. The process yields a variety of bioactive products, including aldehyde-containing phospholipids, which can cross-react with primary amines (i.e. peptides or phospholipid head groups) to yield Schiff base products. We also demonstrate that such oxidized phospholipid products may further react through a post-oxidation chemical pathway involving aldol condensation. EO6, an IgM monoclonal autoantibody to oxidized phospholipids, blocks the uptake of oxidized LDL (OxLDL) by macrophages. Because the epitope(s) of EO6 also blocks the uptake of OxLDL, a series of oxidized phospholipids, their peptide complexes, and their aldol condensates have been synthesized and characterized, and their antigenicity has been determined. This study defines structural motifs of oxidized phospholipids responsible for antigenicity for EO6. Certain monomeric phospholipids containing short chain fatty acids were antigenic whether oxidized or not in the sn-2 position. However, oxidized phospholipids containing sn-1 long chain fatty acids were not antigenic unless the sn-2 oxidized fatty acid contained an aldehyde that first reacted with a peptide yielding a Schiff base or the sn-2 oxidized fatty acid underwent an aldol type self-condensation. Our data indicate that the phosphorylcholine head group is essential for antigenicity, but its availability depends on the oxidized phospholipid conformation. We suggest that upon oxidation, similar reactions occur in phospholipids on the surface of LDL, generating ligands for macrophage recognition. Synthetic imine adducts of oxidized phospholipids of this type are capable of blocking the uptake of OxLDL.