TNF-α promotes early atherosclerosis by increasing transcytosis of LDL across endothelial cells: Crosstalk between NF-κB and PPAR-γ
TNF-α promotes early atherosclerosis by increasing transcytosis of LDL across endothelial cells: Crosstalk between NF-κB and PPAR-γ
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DOI：
10.1016/j.yjmcc.2014.02.012
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发表时间：
2014-07-01
影响因子：
5
通讯作者：
Jin, Si
中科院分区：
文献类型：
--
作者：
Zhang, Youzhi;Yang, Xiaoyan;Jin, Si
肿瘤坏死因子-a （tnf - α）是一种已确定的促动脉粥样硬化因子，但其机制尚不完全清楚。我们探讨了tnf - α是否可以通过增加内皮细胞中脂蛋白（如LDL）的胞吞作用来促进动脉粥样硬化，以及nf - κ B和ppar - γ如何参与这一过程。tnf - α显著增加LDL在人脐静脉内皮细胞（HUVECs）的胞吞作用，并刺激LDL在血管壁内皮下滞留的增加。tnf - α的这些作用不仅被胞吞抑制剂，而且还被nf - κ B抑制剂和ppar - γ抑制剂所阻断。在ApoE（-/-）小鼠中，NF-kappa B和ppar - γ抑制剂均可减轻tnf - α促进的早期动脉粥样硬化变化。NF-kappa B和PPAR-gamma抑制剂可下调tnf - α诱导的NF-kappa B和PPAR-gamma的转录活性。此外，交叉结合活性分析表明，NF-kappa B和PPAR-gamma可以形成含有NF-kappa B P65亚基和PPAR-gamma的活性转录因子复合物。tnf - α刺激的LDL转胞相关蛋白（LDL受体和小窝蛋白-1，-2）的表达增加也被nf - κ B抑制剂和ppar - γ抑制剂阻断。tnf - α通过增加LDL跨内皮细胞的胞吞作用，从而促进LDL在血管壁的滞留，从而促进动脉粥样硬化。在此过程中，NF-kappa B和ppar - γ协同激活，上调转胞相关蛋白的表达。这些观察结果表明，nf - κ B或ppar - γ的抑制剂可用于靶向动脉粥样硬化。(C) 2014 Elsevier Ltd.版权所有。
Tumor necrosis factor-a (TNF-alpha) is an established pro-atherosclerotic factor, but the mechanism is not completely understood. We explored whether TNF-alpha could promote atherosclerosis by increasing the transcytosis of lipoproteins (e.g., LDL) across endothelial cells and how NF-kappa B and PPAR-gamma were involved in this process. TNF-alpha significantly increased the transcytosis of LDL across human umbilical vein endothelial cells (HUVECs) and stimulated an increase of subendothelial retention of LDL in vascular walls. These effects of TNF-alpha were substantially blocked not only by transcytosis inhibitors, but also by NF-kappa B inhibitors and PPAR-gamma inhibitors. In ApoE(-/-) mice, both NF-kappa B and PPAR-gamma inhibitors alleviated the early atherosclerotic changes promoted by TNF-alpha. NF-kappa B and PPAR-gamma inhibitors down-regulated the transcriptional activities of NF-kappa B and PPAR-gamma induced by TNF-alpha. Furthermore, cross-binding activity assay revealed that NF-kappa B and PPAR-gamma could form an active transcription factor complex containing both the NF-kappa B P65 subunit and PPAR-gamma. The increased expressions of LDL transcytosis-related proteins (LDL receptor and caveolin-1, -2) stimulated by TNF-alpha were also blocked by both NF-kappa B inhibitors and PPAR-gamma inhibitors. TNF-alpha promotes atherosclerosis by increasing the LDL transcytosis across endothelial cells and thereby facilitating LDL retention in vascular walls. In this process, NF-kappa B and PPAR-gamma are activated coordinately to up-regulate the expression of transcytosis-related proteins. These observations suggest that inhibitors of either NF-kappa B or PPAR-gamma can be used to target atherosclerosis. (C) 2014 Elsevier Ltd. All rights reserved.