Apolipoprotein CIII-induced THP-1 cell adhesion to endothelial cells involves pertussis toxin-sensitive G protein- and protein kinase Cα-mediated nuclear factor-κB activation
Apolipoprotein CIII-induced THP-1 cell adhesion to endothelial cells involves pertussis toxin-sensitive G protein- and protein kinase Cα-mediated nuclear factor-κB activation
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DOI：
10.1161/01.atv.0000249620.68705.0d
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发表时间：
2007-01-01
影响因子：
8.7
通讯作者：
Sacks, Frank M.
中科院分区：
文献类型：
--
作者：
Kawakami, Akio;Aikawa, Masanori;Sacks, Frank M.
血浆载脂蛋白CIII（apoCIII）可独立预测冠心病（CHD）的风险。我们最近报道apoCIII直接增强人单核细胞与内皮细胞（EC）的粘附，并确定PKC α的激活是增强单核细胞粘附的必要上游事件。本研究测试了apoCIII激活人单核细胞THP-1细胞中的PKC α，导致NF-κ B激活的假设。方法和结果-在PKC激活剂特异性的抑制剂中，磷脂酰胆碱特异性磷脂酶C（PC-PLC）抑制剂D 609限制apoCIII诱导的PKC α激活和THP-1细胞粘附。ApoCIII增加THP-1细胞中的PC-PLC活性，导致PKC α活化。百日咳毒素（PTX）抑制apoCIII诱导的PC-PLC激活和随后的PKC α激活，涉及PTX敏感的G蛋白通路。ApoCIII通过THP-1细胞中的PKC α进一步激活核因子-κ B（NF-κ B）并增加β 1-整联蛋白表达。NF-κ B抑制肽SN 50部分抑制apoCIII诱导的β 1-整联蛋白表达和THP-1细胞粘附。ApoCIII丰富的VLDL有类似的影响apoCIII单独。结论PTX敏感的G蛋白通路参与至关重要的PKC α刺激THP-1细胞暴露于apoCIII，激活NF-κ B，并增加β 1-整联蛋白。这种作用导致单核细胞粘附到内皮细胞上。此外，由于白细胞NF-κ B活化有助于动脉粥样硬化形成的炎症方面，apoCIII可通过单核细胞活化刺激多种炎症反应。
Objective-Plasma apolipoprotein CIII (apoCIII) independently predicts risk for coronary heart disease (CHD). We recently reported that apoCIII directly enhances adhesion of human monocytes to endothelial cells (ECs), and identified the activation of PKC alpha as a necessary upstream event of enhanced monocyte adhesion. This study tested the hypothesis that apoCIII activates PKC alpha in human monocytic THP-1 cells, leading to NF-kappa B activation.Methods and Results-Among inhibitors specific to PKC activators, phosphatidylcholine-specific phospholipase C (PC-PLC) inhibitor D609 limited apoCIII-induced PKC alpha activation and THP-1 cell adhesion. ApoCIII increased PC-PLC activity in THP-1 cells, resulting in PKC alpha activation. Pertussis toxin (PTX) inhibited apoCIII-induced PC-PLC activation and subsequent PKC alpha activation, implicating PTX-sensitive G protein pathway. ApoCIII further activated nuclear factor-kappa B (NF-kappa B) through PKC alpha in THP-1 cells and augmented beta 1-integrin expression. The NF-kappa B inhibitor peptide SN50 partially inhibited apoCIII-induced beta 1-integrin expression and THP-1 cell adhesion. ApoCIII-rich VLDL had similar effects to apoCIII alone.Conclusions-PTX-sensitive G protein pathway participates critically in PKC alpha stimulation in THP-1 cells exposed to apoCIII, activating NF-kappa B, and increasing beta 1-integrin. This action causes monocytic cells to adhere to endothelial cells. Furthermore, because leukocyte NF-kappa B activation contributes to inflammatory aspects of atherogenesis, apoCIII may stimulate diverse inflammatory responses through monocyte activation.