Activation of NADPH oxidase is required for macrophage-mediated oxidation of low-density lipoprotein
Activation of NADPH oxidase is required for macrophage-mediated oxidation of low-density lipoprotein
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DOI：
10.1016/s0026-0495(96)90005-0
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发表时间：
1996-09-01
影响因子：
9.8
通讯作者：
Levy, R
中科院分区：
文献类型：
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作者：
Aviram, M;Rosenblat, M;Levy, R
动脉壁细胞的低密度脂蛋白 (LDL) 氧化是早期动脉粥样硬化形成过程中的一个关键事件，被认为涉及 15-脂氧合酶和/或烟酰胺腺嘌呤二核苷酸磷酸 (NADPH) 氧化酶的激活。我们试图分析这些加氧酶在氧化应激下巨噬细胞介导的 LDL 氧化中的作用。在 1 μmol/L CuSO4 存在下，将 LDL 与 J-774 A.1 巨噬细胞样细胞系或人单核细胞来源的巨噬细胞 (HMDM) 一起孵育，结果证明超氧阴离子会释放到培养基中。在这些条件下，NADPH 氧化酶复合物的胞质蛋白成分 P-47 和 P-67 易位至质膜，表明 LDL 介导的 NADPH 氧化酶复合物激活。在上述实验条件下，巨噬细胞15-脂氧合酶也被激活，这通过向培养基中释放15-羟基-5,8,11,13-二十碳四烯酸（15-HETE）和13-羟基十八碳二烯酸（13-HODE）来确定。在这些条件下，用夹竹桃麻素抑制巨噬细胞 NADPH 氧化酶，或用超氧化物歧化酶 (SOD) 歧化超氧阴离子（NADPH 氧化酶激活的产物），可显着抑制巨噬细胞介导的 LDL 氧化（抑制 61% 至 89%）。佛波醇肉豆蔻酸酯乙酸酯 (PMA) 可引起 J-774 A.1 巨噬细胞中的 NADPH 氧化酶激活，对 15-脂氧合酶活性没有显着影响，但仍会导致细胞介导的 LDL 氧化。最后，来自两名慢性肉芽肿病 (CGD) 患者的 HMDM 缺乏活性 NADPH 氧化酶，但具有几乎正常的 15-脂氧合酶活性，但未能氧化 LDL。因此，我们得出结论，LDL 诱导的 NADPH 氧化酶激活（在氧化应激下）是巨噬细胞介导的 LDL 氧化所必需的，而 15-脂氧合酶的激活可能不足以在这些条件下进行 LDL 氧化。版权所有 (C) 1996 W.B.桑德斯公司
Low-density lipoprotein (LDL) oxidation by arterial wall cells, a key event during early atherogenesis, was suggested to involve the activation of 15-lipoxygenase and/or nicotinamide adenine dinucleotide phosphate (NADPH) oxidase. We sought to analyze the role of these oxygenases in macrophage-mediated oxidation of LDL under oxidative stress. Upon incubation of LDL with the J-774 A.1 macrophage-like cell line or with human monocyte-derived macrophages (HMDM) in the presence of 1 mu mol/L CuSO4, the release of superoxide anions to the medium was demonstrated. Under these conditions, the cytosolic protein components of the NADPH oxidase complex, P-47 and P-67, translocated to the plasma membrane, indicating LDL-mediated activation of the NADPH oxidase complex. Under the above-mentioned experimental conditions, the macrophage 15-lipoxygenase was also activated, as determined by the release of 15-hydroxy-5,8,11,13-eicosatetraenoic acid (15-HETE) and 13-hydroxyoctadecadienoic acid (13-HODE) to the medium. Inhibition of the macrophage NADPH oxidase with apocynin or dismutation of superoxide anions, the product of NADPH oxidase activation, with superoxide dismutase (SOD) significantly inhibited macrophage-mediated oxidation of LDL (by 61% to 89%) under these conditions. Phorbol myristate acetate (PMA), which causes NADPH oxidase activation in J-774 A.1 macrophages, had no significant effect on 15-lipoxygenase activity, but still resulted in cell-mediated oxidation of LDL. Finally, HMDM from two patients with chronic granulomatous disease (CGD) that were shown to lack active NADPH oxidase, but to possess almost normal 15-lipoxygenase activity failed to oxidize LDL. We thus conclude that LDL-induced NADPH oxidase activation (under oxidative stress) is required for macrophage-mediated oxidation of LDL, whereas activation of 15-lipoxygenase may not be sufficient for LDL oxidation under these conditions. Copyright (C) 1996 by W.B. Saunders Company