Abstract 652: ApolipoproteinCIII Induces Expression of Vascular Cell Adhesion Molecule-1 (VCAM-1) in Vascular Endothelial Cells and Increases Adhesion of Monocytic Cells
Background Activation of vascular endothelial cells (ECs) contributes importantly to atherogenesis. Lipoproteins containing apolipoprotein (apo) CIII predict coronary heart disease (CHD). We recently reported that apoCIII may contribute directly to atherogenesis by activating human peripheral monocytes and inducing their adhesion to ECs.
Methods and Results To test the hypothesis that apoCIII induces EC expression of adhesion molecules and promotes monocytic cell adhesion, we treated ECs with apoCIII or apoCIII-rich very low-density lipoprotein (apoCIII-VLDL) (10 mg apoB/dL, 8 hours) before adhesion assays. Endotoxin levels in apoCIII and apoCIII-VLDL were < 0.03 EU/mL. ApoCIII-VLDL increased adhesion of human monocytoid THP-1 cells to EC under static or laminar sheer stress (1.0 dyne/cm2) conditions by 2.1±0.7 fold and 1.7±0.5 fold vs. control, respectively (p<0.05). ApoCIII (10 mg/dL, 8 hours) increased EC expression of vascular cell adhesion molecule-1 (VCAM-1) and intercellular cell adhesion molecule-1 (ICAM-1) proteins (4.9±1.5 fold and 1.4±0.5 fold vs. control, p<0.05). An anti-VCAM-1 neutralizing antibody blocked apoCIII-induced THP-1 cell adhesion. Further, apoCIII activated protein kinase C (PKC) β and nuclear factor-kappa B (NF-κB) activation in ECs. A selective PKCβ inhibitor prevented apoCIII-induced NF-κB activation, VCAM-1 expression, and THP-1 cell adhesion. ApoCIII-VLDL also activated PKCβ and NF-κB in ECs and increased expression of VCAM-1. Pretreatment of ApoCIII-VLDL with anti-apoCIII neutralizing antibody abolished its effect on PKCβ activation.
Conclusion Our findings establish that apoCIII increases VCAM-1 and ICAM-1 expression in ECs by activating PKCβ and NF-κB, suggesting a novel mechanism for EC activation in dyslipidemia. Therefore, apoCIII-VLDL may contribute directly to atherogenesis by triggering EC activation, expression of VCAM-1, and monocyte recruitment.