THE SIMULTANEOUS GENERATION OF SUPEROXIDE AND NITRIC-OXIDE CAN INITIATE LIPID-PEROXIDATION IN HUMAN LOW-DENSITY-LIPOPROTEIN
THE SIMULTANEOUS GENERATION OF SUPEROXIDE AND NITRIC-OXIDE CAN INITIATE LIPID-PEROXIDATION IN HUMAN LOW-DENSITY-LIPOPROTEIN
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DOI：
10.3109/10715769209061085
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发表时间：
1992-01-01
期刊：
影响因子：
--
通讯作者：
MONCADA, S
中科院分区：
文献类型：
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作者：
DARLEYUSMAR, VM;HOGG, N;MONCADA, S
低密度脂蛋白（LDL）的氧化已被证明发生在动物模型和人类动脉粥样硬化病变的动脉壁。负责启动这一过程的氧化剂正在深入研究中，15-脂氧合酶已在此背景下提出。另一种可能性是，动脉壁细胞产生的一氧化氮和超氧化物一起反应形成过氧亚硝酸盐，过氧亚硝酸盐分解形成高活性羟基自由基。在本研究中，我们模拟了同时产生的超氧化物和一氧化氮通过使用sydnonimine，SIN-1，并研究了其对LDL的影响。SIN-1在自氧化过程中释放超氧化物和一氧化氮，导致羟基自由基的形成。我们已经证明，由SIN- 1产生的超氧化物不能参与歧化反应，因为它优先与一氧化氮反应。因此，在SIN-1的自氧化过程中，很少或没有超氧化物或过羟基自由基可用于引发脂质过氧化。我们已经表明，SIN-1能够启动LDL的过氧化反应，并将脂蛋白转化为带更多负电荷的形式。超氧化物歧化酶可完全抑制SIN-1依赖的LDL过氧化反应。硝普钠和S-亚硝基-N-乙酰青霉胺都不能修饰LDL，它们只产生一氧化氮。这些结果与超氧化物和一氧化氮的产物可以氧化动脉壁中的脂蛋白并因此有助于体内动脉粥样硬化的发病机制的假设一致。
Oxidation of low density lipoprotein (LDL) has been shown to occur in the artery wall of atherosclerotic lesions in both animal models and human arteries. The oxidant(s) responsible for initiating this process are under intensive investigation and 15-lipoxygenase has been suggested in this context. Another possibility is that nitric oxide and superoxide, generated by cells present in the artery wall, react together to form peroxynitrite which decomposes to form the highly reactive hydroxyl radical. In the present study we have modelled the simultaneous generation of superoxide and nitric oxide by using the sydnonimine, SIN-1 and have investigated its effects on LDL. SIN-1 liberates both superoxide and nitric oxide during autooxidation resulting in the formation of hydroxyl radicals. We have demonstrated that superoxide generated by SIN- 1 is not available to take part in a dismutation reaction since it reacts preferentially with nitric oxide. It follows, therefore, that during the autooxidation of SIN-1 little or no superoxide, or perhydroxyl radical will be available to initiate lipid peroxidation. We have shown that SIN-1 is capable of initiating the peroxidation of LDL and also converts the lipoprotein to a more negatively charged form. The SIN-1-dependent peroxidation of LDL is completely inhibited by superoxide dismutase which scavenges superoxide. Neither sodium nitroprusside or S-nitroso-n-acetyl penicillamine, which only produce nitric oxide, are able to modify LDL. These results are consistent with the hypothesis that a product of superoxide and nitric oxide could oxidize lipoproteins in the artery wall and so contribute to the pathogenesis of atherosclerosis in vivo.