NF-κB和PPAR-γ交叉对话调控LDL穿胞及其在动脉粥样硬化中的作用
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摘要
目的：高脂血症是动脉粥样硬化（atherosclerosis，AS）发生发展的主要危险因素之一，其中低密度脂蛋白（LDL）在内皮细胞下的滞留被认为是AS的始发因素，而LDL在血管内皮细胞下的滞留主要通过在血管内皮细胞中穿胞（transcytosis）实现。TNF-α是已知能促AS形成与发展的重要炎症介质，但其促AS发生发展的具体机制尚未阐明。在本论文中，我们首先建立体外穿胞模型，观察TNF-α对LDL在人脐静脉内皮细胞（HUVECs）中穿胞的影响及对AS发生发展的影响，并进一步探讨与TNF-α密切相关的两个转录因子核转录因子(NF-κB)和过氧化物酶体增殖物激活受体-γ(PPAR-γ)在该过程中的作用。
方法：通过transwell嵌套培养技术，用FITC标记LDL，将含有6倍浓度未标记的LDL作为竞争组，通过荧光酶标仪检测transwell小室下层液体的荧光密度,并计算其差值来建立HUVECs体外LDL穿胞模型。用建立的体外穿胞模型检测穿胞抑制剂，NF-κB抑制剂以及PPAR-γ抑制剂对TNF-α所引起穿胞的影响；激光共聚焦方法检测LDL在人脐静脉内皮细胞中的摄取量以及在人脐静脉血管壁的滞留量；在ApoE-/-小鼠，用油红O染色检测主动脉根部斑块的形成，用免疫组化方法检测斑块处CD154信号的表达情况。用基于ELISA转录因子活性测定方法检测总蛋白中NF-κB和PPAR-γ的活性；WesternBlot方法检测LDL穿胞相关蛋白LDLR，caveolin-1和caveolin-2的表达。
结果：本文在HUVECs中成功建立了LDL体外穿胞的模型，且发现其具有浓度依赖性。当LDL的浓度从50μg/ml增加到100μg/ml时，LDL穿胞量显著增加，表明LDL的穿胞具有明显的浓度依赖性。在建立的体外穿胞模型中发现，TNF-α能够增加LDL在内皮细胞中的穿胞，而且该作用不仅能被穿胞抑制剂NEM和M-β-CD（MCD）所阻断，而且也能被NF-κB抑制剂Bay-11-7082(Bay)和(PDTC)以及PPAR-γ的抑制剂GW9662,T0070907(T007)所降低。同样，在激光共聚焦实验中发现，穿胞抑制剂NEM和MCD，NF-κB和PPAR-γ的抑制剂也能减少TNF-α引起的LDL颗粒在内皮细胞中的摄取以及血管壁的滞留。在ApoE-/-小鼠，我们发现注射TNF-α能加速血管壁AS斑块的形成，且TNF-α促进早期AS斑块形成的作用不仅能被NEM和MCD这两个穿胞抑制剂所抑制，而且也能被NF-κB抑制剂PDTC,PPAR-γ抑制剂GW9662所抑制。我们进一步研究了CD40配体CD154的表达，其参加早期AS的形成，结果表明NF-κB和PPAR-γ抑制剂能阻止斑块处CD154的表达。用基于ELISA的转录因子活性测定方法发现，TNF-α不仅能够增加NF-κB活性，也能够增加PPAR-γ的活性；NF-κB抑制剂Bay和PDTC不仅抑制NF-κB活性，也能抑制PPAR-γ的活性。同样，PPAR-γ的抑制剂GW9662,T007不仅能逆转TNF-α引起的PPAR-γ活性的增加，也能在一定程度上抑制TNF-α引起的NF-κB活性的增加。采用交叉结合试验进一步探讨NF-κB和PPAR-γ两者之间的相互作用，给予TNF-α刺激后形成的活性转录因子复合物既包含NF-κBP65亚基，也包括PPAR-γ，且该复合体不仅结合NF-κB反应元件（KBRE），也结合PPAR-γ反应元件（PPRE）。在用WesternBlot方法检测LDL穿胞相关蛋白中，TNF-α能够增加低密度脂蛋白受体LDLR，小凹蛋白caveolin-1，caveolin-2的表达，且该作用既能被NF-κB抑制剂所阻断，也能被PPAR-γ抑制剂所拮抗。
结论：LDL穿胞具有浓度依赖性，给临床上高脂血症促发AS提供了重要的实验依据。TNF-α可通过直接刺激LDL在血管内皮细胞穿胞、增加LDL在血管壁滞留进而促进AS的形成。在该过程中，NF-κB和PPAR-γ两个转录因子均被激活并且交叉对话，相互结合形成活性复合物，从而促进LDL穿胞相关蛋白包括LDLR，Caveolin-1，-2的转录和表达，进而促进LDL穿胞和AS的形成。抑制二者中的任一转录因子的激活，均能起到预防和治疗AS的作用。
Objective: Hyperlipidemia is one of the most important causes of atherosclerosis (AS). Numerous reviews have suggested that subendothelial retention of low density lipoprotein (LDL) is the initial steps of AS and the retention of LDL is achieved by the transcytosis of LDL across the vascular endothelial cells. Tumor necrosis factor-a (TNF-a) is an established pro-atherosclerotic factor, but the mechanism is not completely understood. Here we first established the model of the transcytosis in vitro and explored whether or not TNF-a could promote atherosclerosis by directly increasing the transcytosis of LDL particles across human umbilical vein endothelial cells (HUVECs), and further explore the roles of NF-κB and PPAR-γ related with TNF-a in this process.
Methods:In the present study, we developed an in vitro model to investigate the transcytosis of LDL across a tight monolayer of HUVEC cultured in transwell-inserts by using LDL labeled with Fluorescein isothiocyanate (FITC) in the absence or presence of6-fold excess of unlabeled LDL. The effects of TNF-α and inhibitor on the transcytosis of LDL across vascular endothelial cells were also investigated by established the model of the transcytosis; FITC-LDL fluorescence intensity in HUVECs and human umbilical vein was measured by confocal microscope. Aortic roots were stained for lipids with Oil-red O for evaluation of aortic lesions in ApoE-/-mice. CD154signal were used by immunohistochemical analyses. By an ELISA-based transcription activity assay, the TNF-α-stimulated NF-κB and PPAR-y activities in HUVECs were determined. TNF-α-stimulated and inhibitor changes in protein expression of LDLR, Caveolin-land Caveolin-2in HUVECs were measured by Western blot.
Results:With this model the concentration dependent transcytosis of LDL across endothelial cells were characterized in experiments for the first time. When the concentration of LDL increased from50μg/ml to100μg/ml, the amount of LDL transcytosis also increased significantly, exhibiting an apparent concentration dependent manner. By establishing an in-vitro model to assay the transcytosis of LDL across vascular endothelial cells, we first demonstrated that TNF-α could significantly stimulate the transcytosis of LDL across endothelial cells and this effect can blocked not only by the inhibitors of transcytosis, NEM and M-β-CD (MCD), but also by NF-κB inhibitors Bay-11-7082(Bay) and PDTC and PPAR-γ inhibitors GW9662and T0070907(T007). Similarly, in the confocal laser experiments we found that the uptake and retention of TNF-a-stimulated LDL particles were inhibited by transcytosis inhibitors NEM and MCD and the inhibitor of NF-κB and PPAR-γ. In ApoE-/-mice, we found TNF-a injection indeed accelerates the formation of atherosclerotic plaque in the arteries, further supporting the long standing view of TNF-a as a pro-atherogenesis factor. Blockade of the transcytosis of LDL by NEM and MCD substantially prevents the early atherosclerosis changes in artery walls, suggesting a critical role of LDL transcytosis in the initiation or development of AS. Meanwhile, consistent with above in-vitro findings, the TNF-α-promoted early atherosclerotic changes in artery walls were not only reversed by NF-κB inhibitors, PDTC, but also attenuated by PPAR-γ inhibitors, GW9662. In addition, we studied the expression of the CD40ligand, CD154, which is involved in the early atherogenesis and contributes to the initial recruitment of inflammatory cells to damaged endothelium. Our results showed both NF-κB and PPAR-γ inhibitors lowered the CD154expression in plaque which was substantially elevated by TNF-α in ApoE-/-mice. By using an ELISA-based transcriptional factor-DNA binding activity assay, we found TNF-α could significantly activate NF-κB, howeve, the activity of PPAR-γ was also up-regulated by TNF-α. NF-κB inhibitors, Bay and PDTC primarily prevented the TNF-a-stimulated NF-κB activation, but also reversed the TNF-a-stimulated PPAR-γ activity to some extent. Likewise, PPAR-γ inhibitors, GW9662and T007almost completely abolished the TNF-α-stimulated PPAR-γ activation, but also blocked the TNF-a-stimulated NF-κB activity. To further illustrate the relationship of NF-κB and PPAR-γ transcription factor, we found that NF-κB and PPAR-γ could form an active transcriptional compound which include NF-κB P65subunit and PPAR-γ and bind with NF-κB response elements (KBRE) and PPAR-γ response elements (PPRE) respectively, and promote each other's activation after TNF-a stimulation by cross-binding tests. We found TNF-α could significantly up-regulate the expression of low density lipoprotein protein receptor (LDLR) and caveolae protein caveolin-1, caveolin-2, and this effect was reduced by both NF-κB and PPAR-γ inhibitors. Inhibition of one of the activation of two transcription factors, can play the role of prevention and treatment of the development of AS.
Conclusion:The transcytosis of LDL exhibits a concentration dependent manner and is the theoretical basis of the increased risk of hyperlipidemia in AS. TNF-α promotes AS by directly increasing the LDL transcytosis across endothelial cells and LDL retention in the vascular wall. In this process, NF-κB and PPAR-γ are activated, enhancing each other's activation and form the active complexes to up-regulate the expression of proteins associated with LDL transcytosis, including LDLR, Caveolin-1and-2, thereby promoting the transcytosis of LDL and progression of AS in vascular walls.
方法：通过transwell嵌套培养技术，用FITC标记LDL，将含有6倍浓度未标记的LDL作为竞争组，通过荧光酶标仪检测transwell小室下层液体的荧光密度,并计算其差值来建立HUVECs体外LDL穿胞模型。用建立的体外穿胞模型检测穿胞抑制剂，NF-κB抑制剂以及PPAR-γ抑制剂对TNF-α所引起穿胞的影响；激光共聚焦方法检测LDL在人脐静脉内皮细胞中的摄取量以及在人脐静脉血管壁的滞留量；在ApoE-/-小鼠，用油红O染色检测主动脉根部斑块的形成，用免疫组化方法检测斑块处CD154信号的表达情况。用基于ELISA转录因子活性测定方法检测总蛋白中NF-κB和PPAR-γ的活性；WesternBlot方法检测LDL穿胞相关蛋白LDLR，caveolin-1和caveolin-2的表达。
结果：本文在HUVECs中成功建立了LDL体外穿胞的模型，且发现其具有浓度依赖性。当LDL的浓度从50μg/ml增加到100μg/ml时，LDL穿胞量显著增加，表明LDL的穿胞具有明显的浓度依赖性。在建立的体外穿胞模型中发现，TNF-α能够增加LDL在内皮细胞中的穿胞，而且该作用不仅能被穿胞抑制剂NEM和M-β-CD（MCD）所阻断，而且也能被NF-κB抑制剂Bay-11-7082(Bay)和(PDTC)以及PPAR-γ的抑制剂GW9662,T0070907(T007)所降低。同样，在激光共聚焦实验中发现，穿胞抑制剂NEM和MCD，NF-κB和PPAR-γ的抑制剂也能减少TNF-α引起的LDL颗粒在内皮细胞中的摄取以及血管壁的滞留。在ApoE-/-小鼠，我们发现注射TNF-α能加速血管壁AS斑块的形成，且TNF-α促进早期AS斑块形成的作用不仅能被NEM和MCD这两个穿胞抑制剂所抑制，而且也能被NF-κB抑制剂PDTC,PPAR-γ抑制剂GW9662所抑制。我们进一步研究了CD40配体CD154的表达，其参加早期AS的形成，结果表明NF-κB和PPAR-γ抑制剂能阻止斑块处CD154的表达。用基于ELISA的转录因子活性测定方法发现，TNF-α不仅能够增加NF-κB活性，也能够增加PPAR-γ的活性；NF-κB抑制剂Bay和PDTC不仅抑制NF-κB活性，也能抑制PPAR-γ的活性。同样，PPAR-γ的抑制剂GW9662,T007不仅能逆转TNF-α引起的PPAR-γ活性的增加，也能在一定程度上抑制TNF-α引起的NF-κB活性的增加。采用交叉结合试验进一步探讨NF-κB和PPAR-γ两者之间的相互作用，给予TNF-α刺激后形成的活性转录因子复合物既包含NF-κBP65亚基，也包括PPAR-γ，且该复合体不仅结合NF-κB反应元件（KBRE），也结合PPAR-γ反应元件（PPRE）。在用WesternBlot方法检测LDL穿胞相关蛋白中，TNF-α能够增加低密度脂蛋白受体LDLR，小凹蛋白caveolin-1，caveolin-2的表达，且该作用既能被NF-κB抑制剂所阻断，也能被PPAR-γ抑制剂所拮抗。
结论：LDL穿胞具有浓度依赖性，给临床上高脂血症促发AS提供了重要的实验依据。TNF-α可通过直接刺激LDL在血管内皮细胞穿胞、增加LDL在血管壁滞留进而促进AS的形成。在该过程中，NF-κB和PPAR-γ两个转录因子均被激活并且交叉对话，相互结合形成活性复合物，从而促进LDL穿胞相关蛋白包括LDLR，Caveolin-1，-2的转录和表达，进而促进LDL穿胞和AS的形成。抑制二者中的任一转录因子的激活，均能起到预防和治疗AS的作用。
Objective: Hyperlipidemia is one of the most important causes of atherosclerosis (AS). Numerous reviews have suggested that subendothelial retention of low density lipoprotein (LDL) is the initial steps of AS and the retention of LDL is achieved by the transcytosis of LDL across the vascular endothelial cells. Tumor necrosis factor-a (TNF-a) is an established pro-atherosclerotic factor, but the mechanism is not completely understood. Here we first established the model of the transcytosis in vitro and explored whether or not TNF-a could promote atherosclerosis by directly increasing the transcytosis of LDL particles across human umbilical vein endothelial cells (HUVECs), and further explore the roles of NF-κB and PPAR-γ related with TNF-a in this process.
Methods:In the present study, we developed an in vitro model to investigate the transcytosis of LDL across a tight monolayer of HUVEC cultured in transwell-inserts by using LDL labeled with Fluorescein isothiocyanate (FITC) in the absence or presence of6-fold excess of unlabeled LDL. The effects of TNF-α and inhibitor on the transcytosis of LDL across vascular endothelial cells were also investigated by established the model of the transcytosis; FITC-LDL fluorescence intensity in HUVECs and human umbilical vein was measured by confocal microscope. Aortic roots were stained for lipids with Oil-red O for evaluation of aortic lesions in ApoE-/-mice. CD154signal were used by immunohistochemical analyses. By an ELISA-based transcription activity assay, the TNF-α-stimulated NF-κB and PPAR-y activities in HUVECs were determined. TNF-α-stimulated and inhibitor changes in protein expression of LDLR, Caveolin-land Caveolin-2in HUVECs were measured by Western blot.
Results:With this model the concentration dependent transcytosis of LDL across endothelial cells were characterized in experiments for the first time. When the concentration of LDL increased from50μg/ml to100μg/ml, the amount of LDL transcytosis also increased significantly, exhibiting an apparent concentration dependent manner. By establishing an in-vitro model to assay the transcytosis of LDL across vascular endothelial cells, we first demonstrated that TNF-α could significantly stimulate the transcytosis of LDL across endothelial cells and this effect can blocked not only by the inhibitors of transcytosis, NEM and M-β-CD (MCD), but also by NF-κB inhibitors Bay-11-7082(Bay) and PDTC and PPAR-γ inhibitors GW9662and T0070907(T007). Similarly, in the confocal laser experiments we found that the uptake and retention of TNF-a-stimulated LDL particles were inhibited by transcytosis inhibitors NEM and MCD and the inhibitor of NF-κB and PPAR-γ. In ApoE-/-mice, we found TNF-a injection indeed accelerates the formation of atherosclerotic plaque in the arteries, further supporting the long standing view of TNF-a as a pro-atherogenesis factor. Blockade of the transcytosis of LDL by NEM and MCD substantially prevents the early atherosclerosis changes in artery walls, suggesting a critical role of LDL transcytosis in the initiation or development of AS. Meanwhile, consistent with above in-vitro findings, the TNF-α-promoted early atherosclerotic changes in artery walls were not only reversed by NF-κB inhibitors, PDTC, but also attenuated by PPAR-γ inhibitors, GW9662. In addition, we studied the expression of the CD40ligand, CD154, which is involved in the early atherogenesis and contributes to the initial recruitment of inflammatory cells to damaged endothelium. Our results showed both NF-κB and PPAR-γ inhibitors lowered the CD154expression in plaque which was substantially elevated by TNF-α in ApoE-/-mice. By using an ELISA-based transcriptional factor-DNA binding activity assay, we found TNF-α could significantly activate NF-κB, howeve, the activity of PPAR-γ was also up-regulated by TNF-α. NF-κB inhibitors, Bay and PDTC primarily prevented the TNF-a-stimulated NF-κB activation, but also reversed the TNF-a-stimulated PPAR-γ activity to some extent. Likewise, PPAR-γ inhibitors, GW9662and T007almost completely abolished the TNF-α-stimulated PPAR-γ activation, but also blocked the TNF-a-stimulated NF-κB activity. To further illustrate the relationship of NF-κB and PPAR-γ transcription factor, we found that NF-κB and PPAR-γ could form an active transcriptional compound which include NF-κB P65subunit and PPAR-γ and bind with NF-κB response elements (KBRE) and PPAR-γ response elements (PPRE) respectively, and promote each other's activation after TNF-a stimulation by cross-binding tests. We found TNF-α could significantly up-regulate the expression of low density lipoprotein protein receptor (LDLR) and caveolae protein caveolin-1, caveolin-2, and this effect was reduced by both NF-κB and PPAR-γ inhibitors. Inhibition of one of the activation of two transcription factors, can play the role of prevention and treatment of the development of AS.
Conclusion:The transcytosis of LDL exhibits a concentration dependent manner and is the theoretical basis of the increased risk of hyperlipidemia in AS. TNF-α promotes AS by directly increasing the LDL transcytosis across endothelial cells and LDL retention in the vascular wall. In this process, NF-κB and PPAR-γ are activated, enhancing each other's activation and form the active complexes to up-regulate the expression of proteins associated with LDL transcytosis, including LDLR, Caveolin-1and-2, thereby promoting the transcytosis of LDL and progression of AS in vascular walls.
引文
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