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 (4.9Ϯ1.5-fold and 1.4Ϯ0.5-fold versus control, respectively). Furthermore, apoCIII remarkably increased membranebound protein kinase C (PKC) ␤ in ECs, indicating activation. A selective inhibitor of PKC␤ prevented the rise in VCAM-1 and THP-1 cell adhesion to ECs. Moreover, exposure of ECs to apoCIII induced nuclear factor-B (NF-B) activation. PKC␤ inhibition abolished apoCIII-induced NF-B activation, and NF-B inhibition reduced expression of VCAM-1, each resulting in reduced THP-1 cell adhesion. ApoCIII-rich VLDL also activated PKC␤ and NF-B in ECs and increased expression of VCAM-1. Pretreatment of ApoCIII-rich VLDL with anti-apoCIII neutralizing antibody abolished its effect on PKC␤ activation. Conclusions-Our findings provide the first evidence that apoCIII increases VCAM-1 and ICAM-1 expression in ECs by activating PKC␤ and NF-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.

Background-Lipoproteins containing apolipoprotein (apo) CIII predict coronary heart disease and associate with components of the metabolic syndrome. ApoCIII inhibits lipoprotein catabolism in plasma. However, it is unknown whether apoCIII itself, or in association with VLDL, LDL, or HDL, directly affects atherogenic mechanisms in vascular cells. Thus, we investigated the direct effect of lipoproteins that do or do not have apoCIII, and apoCIII itself, on adhesion of THP-1 cells, a human monocytic cell line, to vascular endothelial cells (ECs). Methods and Results-VLDL CIIIϩ and LDL CIII ϩ (100 g apoB/mL) from fasting plasma of 18 normolipidemic volunteers increased THP-1 cell adhesion to ECs under static conditions by 2.4Ϯ0.3-fold and 1.8Ϯ0.7-fold, respectively (PϽ0.01), whereas VLDL or LDL without apoCIII did not affect THP-1 cell adhesion. ApoCIII (100 g/mL), but not apoCI, apoCII or apoE, also increased THP-1 cell adhesion by 2.1Ϯ0.6-fold. Studies with human peripheral blood monocytes yielded similar results. ApoCIII also had strong proadhesive effects under shear flow conditions. VLDL CIII ϩ , LDL CIII ϩ , or apoCIII itself activated PKC␣ and RhoA in THP-1 cells, which resulted in ␤1-integrin activation and enhancement of THP-1 cell adhesion. Interestingly, HDL CIII ϩ did not affect THP-1 cell adhesion, whereas HDL without apoCIII decreased their adhesion. Conclusions-ApoB lipoproteins that contain apoCIII increase THP-1 cell adhesion to ECs via PKC␣ and RhoA-mediated ␤1-integrin activation. These results indicate that apoCIII not only modulates lipoprotein metabolism but also may directly contribute to the development of atherosclerosis. (Circulation. 2006;113:691-700.)