ANGIOTENSIN-II STIMULATES MACROPHAGE-MEDIATED OXIDATION OF LOW-DENSITY LIPOPROTEINS
ANGIOTENSIN-II STIMULATES MACROPHAGE-MEDIATED OXIDATION OF LOW-DENSITY LIPOPROTEINS
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DOI：
10.1016/0021-9150(94)05514-j
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发表时间：
1995-06-01
期刊：
影响因子：
5.3
通讯作者：
AVIRAM, M
中科院分区：
文献类型：
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作者：
KEIDAR, S;KAPLAN, M;AVIRAM, M
血浆肾素活性高的高血压患者心肌梗塞的发病率增加，而从高血压患者获得的低密度脂蛋白（LDL）则证明氧化敏感性增加。由于动脉粥样硬化病变区域存在脂质过氧化，我们试图在体外和体内分析血管紧张素 II (AN-II) 对 LDL 氧化的影响。 J-774 A.1 巨噬细胞样细胞系或小鼠腹膜巨噬细胞 (MPM) 与 AN-II (10(-7)M) 在 37°C 预孵育 1 小时，然后添加 LDL 进一步孵育 18 小时，导致巨噬细胞介导的 LDL 氧化显着增加（分别增加 55% 和 19%）。类似地，与注射盐水的小鼠相比，将 LDL 与注射 AN-II 的小鼠采集的 MPM 一起孵育，导致脂蛋白氧化显着增加高达 90%。在体外和体内研究中，对 MPM 本身细胞脂质过氧化的分析表明，巨噬细胞脂质过氧化分别增加了 25% 或 90%。 AN-II 介导的细胞脂质过氧化的机制涉及 AN-II 与其巨噬细胞上的受体（萨拉拉辛）的结合。 AN-II 受体拮抗剂可完全抑制这种作用。磷脂酶 A(2)、C 和 D 抑制剂显着减少巨噬细胞脂质过氧化，表明磷脂代谢物参与 AN-II 介导的巨噬细胞脂质过氧化。激活磷脂酶的细胞外钙离子对于 AN-II 介导的巨噬细胞脂质过氧化也是必需的，因为钙通道阻滞剂显着抑制细胞脂质过氧化。最后，使用加氧酶抑制剂研究了参与 AN-II 介导的细胞脂质过氧化作用的氧化剂和加氧酶的性质。研究发现血管紧张素 II 介导的巨噬细胞脂质过氧化涉及细胞 NADPH 氧化酶和 15-脂肪加氧酶的作用。我们得出的结论是，AN-II 刺激继发于细胞脂质过氧化的巨噬细胞介导的 LDL 氧化，这可能在高血压患者中发现的加速动脉粥样硬化中发挥作用。
Increased incidence of myocardial infarction was found in hypertensive patients with high plasma renin activity and increased susceptibility to oxidation was demonstrated in low density lipoprotein (LDL) that was obtained from hypertensive patients. As lipid peroxidation was demonstrated in areas of the atherosclerotic lesion, we sought to analyze the effect of angiotensin II (AN-II) on LDL oxidation, both in vitro and in vivo. Preincubation of J-774 A.1 macrophage-like cell line or mouse peritoneal macrophages (MPM) with AN-II (10(-7)M) for 1 h at 37 degrees C, followed by the addition of LDL for a further 18 h of incubation, resulted in a substantial increase in macrophage-mediated oxidation of LDL (by 55% and 19%, respectively). Similarly, incubation of LDL with MPM harvested from AN-II-injected mice resulted in a substantially increased oxidation of the lipoprotein by up to 90% in comparison to saline-injected mice. Analysis of cellular lipid peroxidation in the MPM themselves, in both the in vitro and the in vivo studies, revealed a 25% or 90% increased macrophage lipid peroxidation, respectively. The mechanism of AN-II-mediated cellular lipid peroxidation involved AN-II binding to its receptor on macrophages as saralasin. an AN-II receptor antagonist, completely inhibited this effect. Inhibitors of phospholipases A(2), C and D substantially reduced macrophage lipid peroxidation, suggesting the involvement of phospholipid metabolites in AN-II-mediated macrophage lipid peroxidation. Extracellular calcium ions, which activate phospholipases, were also essential for AN-II-mediated macrophage lipid peroxidation since calcium channel blockers substantially inhibited cellular lipid peroxidation. Finally, the nature of the oxidant and oxygenase involved in AN-II-mediated cellular lipid peroxidation was studied using oxygenase inhibitors. Angiotensin II-mediated macrophage lipid peroxidation was found to involve the action of cellular NADPH oxidase as well as 15-lypoxygenase. We conclude that AN-II stimulates macrophage-mediated oxidation of LDL secondary to cellular lipid peroxidation, and this may have a role in the accelerated atherosclerosis found in hypertensive patients.