Kawakami Akio, Aikawa Masanori, Alcaide Pilar, Luscinskas Francis W, Libby Peter, Sacks Frank M
Department of Nutrition, Harvard School of Public Health, 665 Huntington Ave, Boston, MA 02115, USA.
Circulation. 2006 Aug 15;114(7):681-7. doi: 10.1161/CIRCULATIONAHA.106.622514. Epub 2006 Aug 7.
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.
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/cm2). 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 PKCbeta prevented the rise in VCAM-1 and THP-1 cell adhesion to ECs. Moreover, exposure of ECs to apoCIII induced nuclear factor-kappaB (NF-kappaB) activation. PKCbeta inhibition abolished apoCIII-induced NF-kappaB activation, and NF-kappaB inhibition reduced expression of VCAM-1, each resulting in reduced THP-1 cell adhesion. ApoCIII-rich VLDL also activated PKCbeta and NF-kappaB in ECs and increased expression of VCAM-1. Pretreatment of ApoCIII-rich VLDL with anti-apoCIII neutralizing antibody abolished its effect on PKCbeta activation.
Our findings provide the first evidence that apoCIII increases VCAM-1 and ICAM-1 expression in ECs by activating PKCbeta and NF-kappaB, 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.
血管内皮细胞（ECs）的激活在动脉粥样硬化形成和斑块不稳定中起重要作用。含载脂蛋白CIII（apoCIII）的脂蛋白可预测冠心病（CHD）。我们最近报道apoCIII对人单核细胞有促炎作用。在本研究中，我们探寻apoCIII对ECs黏附分子表达的直接影响，这会导致单核细胞黏附。
用apoCIII或富含apoCIII的极低密度脂蛋白（VLDL）处理ECs，会使人类单核THP-1细胞在静态条件或层流切应力（1.0达因/平方厘米）下黏附于它们。apoCIII增加了血管细胞黏附分子-1（VCAM-1）蛋白和细胞间黏附分子-1（ICAM-1）蛋白在ECs中的表达（分别比对照高4.9±1.5倍和1.4±0.5倍）。此外，apoCIII显著增加了ECs中膜结合蛋白激酶C（PKC）β，表明其被激活。PKCβ的选择性抑制剂可阻止VCAM-1的升高以及THP-1细胞对ECs的黏附。此外，将ECs暴露于apoCIII会诱导核因子-κB（NF-κB）激活。PKCβ抑制消除了apoCIII诱导的NF-κB激活，而NF-κB抑制降低了VCAM-1的表达，每种情况均导致THP-1细胞黏附减少。富含apoCIII的VLDL也激活了ECs中的PKCβ和NF-κB，并增加了VCAM-1的表达。用抗apoCIII中和抗体预处理富含apoCIII的VLDL可消除其对PKCβ激活的作用。
我们的发现首次证明apoCIII通过激活PKCβ和NF-κB增加ECs中VCAM-1和ICAM-1的表达，提示了血脂异常诱导EC激活的新机制。因此，富含apoCIII的VLDL可能通过激活ECs并吸引单核细胞至其而直接促进动脉粥样硬化形成。
