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

Abstract

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 PKCα as a necessary upstream event of enhanced monocyte adhesion. This study tested the hypothesis that apoCIII activates PKCα in human monocytic THP-1 cells, leading to NF-κB activation. METHODS AND RESULTS - Among inhibitors specific to PKC activators, phosphatidylcholine-specific phospholipase C (PC-PLC) inhibitor D609 limited apoCIII-induced PKCα activation and THP-1 cell adhesion. ApoCIII increased PC-PLC activity in THP-1 cells, resulting in PKCα activation. Pertussis toxin (PTX) inhibited apoCIII-induced PC-PLC activation and subsequent PKCα activation, implicating PTX-sensitive G protein pathway. ApoCIII further activated nuclear factor-κB (NF-κB) through PKCα in THP-1 cells and augmented β1-integrin expression. The NF-κB inhibitor peptide SN50 partially inhibited apoCIII-induced β1-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 PKCα stimulation in THP-1 cells exposed to apoCIII, activating NF-κB, and increasing β1-integrin. This action causes monocytic cells to adhere to endothelial cells. Furthermore, because leukocyte NF-κB activation contributes to inflammatory aspects of atherogenesis, apoCIII may stimulate diverse inflammatory responses through monocyte activation. © 2007 American Heart Association, Inc.