Apolipoprotein CIII induces expression of vascular cell adhesion molecule-1 in vascular endothelial cells and increases adhesion of monocytic cells
Apolipoprotein CIII induces expression of vascular cell adhesion molecule-1 in vascular endothelial cells and increases adhesion of monocytic cells
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DOI：
10.1161/circulationaha.106.622514
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发表时间：
2006-08-15
期刊：
影响因子：
37.8
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.
背景 - 血管内皮细胞 (EC) 的激活在动脉粥样硬化形成和斑块不稳定中发挥着重要作用。含有载脂蛋白 CIII (apoCIII) 的脂蛋白可预测冠心病 (CHD)。我们最近报道 apoCIII 对人类单核细胞具有促炎作用。在本研究中，我们寻找 apoCIII 对 EC 粘附分子表达的直接影响，从而导致单核细胞粘附。方法和结果 - 用 apoCIII 或富含 apoCIII 的 VLDL 处理 EC，导致人单核 THP-1 细胞在静态条件下或在层流剪切应力 (1.0 dyne/cm(2)) 下粘附到它们。 ApoCIII 增加血管细胞粘附分子 1 (VCAM-1) 蛋白和细胞间细胞粘附分子 1 (ICAM-1) 蛋白的 EC 表达（分别是对照的 4.9 +/- 1.5 倍和 1.4 +/- 0.5 倍）。此外，apoCIII 显着增加 EC 中的膜结合蛋白激酶 C (PKC) β，表明激活。 PKC beta 的选择性抑制剂可阻止 VCAM-1 和 THP-1 细胞与 EC 粘附的增加。此外，ECs 暴露于 apoCIII 会诱导核因子 kappa B (NF-kappa B) 激活。 PKC beta 抑制消除了 apoCIII 诱导的 NF-kappa B 激活，而 NF-kappa B 抑制则减少了 VCAM-1 的表达，从而导致 THP-1 细胞粘附减少。富含 ApoCIII 的 VLDL 还激活 EC 中的 PKC beta 和 NF-κ B，并增加 VCAM-1 的表达。用抗 apoCIII 中和抗体预处理富含 ApoCIII 的 VLDL，消除了其对 PKC β 激活的影响。结论 - 我们的研究结果提供了第一个证据，表明 apoCIII 通过激活 PKC β 和 NF-κ B 增加 EC 中的 VCAM-1 和 ICAM-1 表达，表明血脂异常诱导 EC 激活的新机制。因此，富含 apoCIII 的 VLDL 可能通过激活 EC 并将单核细胞募集到其中，直接导致动脉粥样硬化形成。
Background - Activation of vascular endothelial cells (ECs) plays an important role in atherogenesis and plaque instability. Lipoproteins containing apolipoprotein CIII (apoCIII) predict coronary heart disease (CHD). We recently reported that apoCIII has a proinflammatory effect on human monocytes. In this study, we looked for a direct effect of apoCIII on EC expression of adhesion molecules, leading to monocytic cell adhesion.Methods and Results - Treatment of ECs with apoCIII or apoCIII-rich VLDL caused human monocytic THP-1 cells to adhere to them under static condition or under laminar sheer stress (1.0 dyne/cm(2)). ApoCIII increased EC expression of vascular cell adhesion molecule-1 (VCAM-1) protein and intercellular cell adhesion molecule-1 (ICAM-1) protein (4.9 +/- 1.5-fold and 1.4 +/- 0.5-fold versus control, respectively). Furthermore, apoCIII remarkably increased membrane-bound protein kinase C (PKC) beta in ECs, indicating activation. A selective inhibitor of PKC beta prevented the rise in VCAM-1 and THP-1 cell adhesion to ECs. Moreover, exposure of ECs to apoCIII induced nuclear factor-kappa B (NF-kappa B) activation. PKC beta inhibition abolished apoCIII-induced NF-kappa B activation, and NF-kappa B inhibition reduced expression of VCAM-1, each resulting in reduced THP-1 cell adhesion. ApoCIII-rich VLDL also activated PKC beta and NF-kappa B in ECs and increased expression of VCAM-1. Pretreatment of ApoCIII-rich VLDL with anti-apoCIII neutralizing antibody abolished its effect on PKC beta activation.Conclusions - Our findings provide the first evidence that apoCIII increases VCAM-1 and ICAM-1 expression in ECs by activating PKC beta and NF-kappa B, suggesting a novel mechanism for EC activation induced by dyslipidemia. Therefore, apoCIII-rich VLDL may contribute directly to atherogenesis by activating ECs and recruiting monocytes to them.