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首页> 外文期刊>Aging cell. >Relation between TLR4/NF-B signaling pathway activation by 27-hydroxycholesterol and 4-hydroxynonenal, and atherosclerotic plaque instability
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Relation between TLR4/NF-B signaling pathway activation by 27-hydroxycholesterol and 4-hydroxynonenal, and atherosclerotic plaque instability

机译：27-羟基胆固醇和4-羟基壬烯醛激活TLR4 / NF-B信号通路与动脉粥样硬化斑块不稳定性之间的关系

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摘要

It is now thought that atherosclerosis, although due to increased plasma lipids, is mainly the consequence of a complicated inflammatory process, with immune responses at the different stages of plaque development. Increasing evidence points to a significant role of Toll-like receptor 4 (TLR4), a key player in innate immunity, in the pathogenesis of atherosclerosis. This study aimed to determine the effects on TLR4 activation of two reactive oxidized lipids carried by oxidized low-density lipoproteins, the oxysterol 27-hydroxycholesterol (27-OH) and the aldehyde 4-hydroxynonenal (HNE), both of which accumulate in atherosclerotic plaques and play a key role in the pathogenesis of atherosclerosis. Secondarily, it examined their potential involvement in mediating inflammation and extracellular matrix degradation, the hallmarks of high-risk atherosclerotic unstable plaques. In human promonocytic U937 cells, both 27-OH and HNE were found to enhance cell release of IL-8, IL-1, and TNF- and to upregulate matrix metalloproteinase-9 (MMP-9) via TLR4/NF-B-dependent pathway; these actions may sustain the inflammatory response and matrix degradation that lead to atherosclerotic plaque instability and to their rupture. Using specific antibodies, it was also demonstrated that these inflammatory cytokines increase MMP-9 upregulation, thus enhancing the release of this matrix-degrading enzyme by macrophage cells and contributing to plaque instability. These innovative results suggest that, by accumulating in atherosclerotic plaques, the two oxidized lipids may contribute to plaque instability and rupture. They appear to do so by sustaining the release of inflammatory molecules and MMP-9 by inflammatory and immune cells, for example, macrophages, through activation of TLR4 and its NF-B downstream signaling.
机译：现在认为动脉粥样硬化虽然是由于血浆脂质增加引起的，但主要是复杂的炎症过程的结果，在斑块形成的不同阶段具有免疫应答。越来越多的证据表明，Toll样受体4（TLR4）是先天免疫的关键参与者，在动脉粥样硬化的发病机理中起着重要作用。这项研究旨在确定由氧化的低密度脂蛋白携带的两种反应性氧化脂质TLR4活化的影响，其中氧化固醇27-羟基胆固醇（27-OH）和醛4-羟基壬烯醛（HNE）都积聚在动脉粥样硬化斑块中并在动脉粥样硬化的发病机理中起关键作用。其次，它检查了它们在介导炎症和细胞外基质降解方面的潜在作用，这是高风险的动脉粥样硬化不稳定斑块的标志。在人类原核单核细胞U937细胞中，发现27-OH和HNE均可通过TLR4 / NF-B依赖来增强IL-8，IL-1和TNF-的细胞释放并上调基质金属蛋白酶9（MMP-9）。途径这些作用可能会维持炎症反应和基质降解，从而导致动脉粥样硬化斑块不稳定和破裂。使用特异性抗体，还证明了这些炎性细胞因子增加了MMP-9的上调，从而增强了巨噬细胞释放这种基质降解酶的能力，并导致斑块不稳定。这些创新的结果表明，通过在动脉粥样硬化斑块中积累，两种氧化脂质可能会导致斑块不稳定和破裂。它们似乎是通过激活TLR4及其NF-B下游信号传导来维持炎症分子和免疫细胞（例如巨噬细胞）释放炎症分子和MMP-9的。

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