3-chlorotyrosine, a specific marker of myeloperoxidase-catalyzed oxidation, is markedly elevated in low density lipoprotein isolated from human atherosclerotic intima
3-chlorotyrosine, a specific marker of myeloperoxidase-catalyzed oxidation, is markedly elevated in low density lipoprotein isolated from human atherosclerotic intima
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DOI：
10.1172/jci119379
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发表时间：
1997-05-01
影响因子：
15.9
通讯作者：
Heinecke, JW
中科院分区：
文献类型：
--
作者：
Hazen, SL;Heinecke, JW
低密度脂蛋白的氧化可能在动脉粥样硬化形成中起关键作用，但促进体内氧化的机制仍然知之甚少。我们已经探索了其中一个途径涉及髓过氧化物酶的可能性，髓过氧化物酶是一种由吞噬细胞分泌的血红素蛋白。髓过氧化物酶是人类已知的唯一一种能产生强氧化剂--次氯酸的酶，在生理卤化物浓度下，暴露于髓过氧化物酶-H_2O_2-氯-体系中的低密度脂蛋白将其蛋白酪氨酸残基氯化，用试剂高氯化处理低密度脂蛋白可形成3-氯酪氨酸，暗示高氯化血红素是酶反应途径中的中间产物。相比之下，在被羟基、铜、铁、氯化高铁、葡萄糖、过氧亚硝酸盐、辣根过氧化物酶、乳过氧化物酶或脂肪氧合酶氧化的低密度脂蛋白中，3-氯酪氨酸是检测不到的。为了探讨髓过氧化物酶在体内促进低密度脂蛋白氧化的作用，我们使用稳定同位素稀释气相色谱-质谱法对人主动脉组织和动脉粥样硬化病变中分离的低密度脂蛋白中的3-氯酪氨酸进行了定量。血管手术中动脉粥样硬化组织中的3-氯酪氨酸水平是正常主动脉内膜的6倍。此外，从动脉粥样硬化内膜分离的低密度脂蛋白中的3-氯酪氨酸水平是循环低密度脂蛋白的30倍。对人体动脉粥样硬化病变中3-氯酪氨酸的检测表明，吞噬细胞的髓过氧化物酶系统催化的卤化反应构成了体内蛋白质氧化的一条途径，这些发现提出了髓过氧化物酶-H_2O_2-氯-系统在将低密度脂蛋白转化为动脉粥样硬化形式中起关键作用的可能性。
Oxidation of LDL may be of pivotal importance in atherogenesis, but the mechanisms that promote oxidation in vivo remain poorly understood. We have explored the possibility that one pathway involves myeloperoxidase, a heme protein secreted by phagocytes. Myeloperoxidase is the only human enzyme known to generate hypochlorous acid (HOCl), a potent oxidizing agent, at physiological halide concentrations, LDL exposed to the complete myeloperoxidase-H2O2-Cl- system underwent chlorination of its protein tyrosyl residues, Treatment of LDL with reagent HOCl resulted in 3-chlorotyrosine formation, implicating HOCl as an intermediate in the enzymatic reaction pathway, In contrast, 3-chlorotyrosine was undetectable in LDL oxidized by hydroxyl radical, copper, iron, hemin, glucose, peroxynitrite, horseradish peroxidase, lactoperoxidase, or lipoxygenase, These results indicate that 3-chlorotyrosine is a specific marker for LDL oxidation by myeloperoxidase. To address the role of myeloperoxidase in promoting LDL oxidation in vivo, we used stable isotope dilution gas chromatography-mass spectrometry to quantify 3-chlorotyrosine in human aortic tissue and in LDL isolated from atherosclerotic lesions. The level of 3-chlorotyrosine in atherosclerotic tissue obtained during vascular surgery was sixfold higher than that of normal aortic intima. Moreover, the level of 3-chlorotyrosine was 30-fold higher in LDL isolated from atherosclerotic intima compared with circulating LDL, The detection of 3-chlorotyrosine in human atherosclerotic lesions indicates that halogenation reactions catalyzed by the myeloperoxidase system of phagocytes constitute one pathway for protein oxidation in vivo, These findings raise the possibility that the myeloperoxidase-H2O2-Cl- system plays a critical role in converting LDL into an atherogenic form.