Apolipoprotein CIII-induced THP-1 cell adhesion to endothelial cells involves pertussis toxin-sensitive G protein- and protein kinase C alpha-mediated nuclear factor-kappaB activation

Arterioscler Thromb Vasc Biol. 2007 Jan;27(1):219-25. doi: 10.1161/01.ATV.0000249620.68705.0d. Epub 2006 Oct 12.

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 PKC alpha as a necessary upstream event of enhanced monocyte adhesion. This study tested the hypothesis that apoCIII activates PKC alpha in human monocytic THP-1 cells, leading to NF-kappaB activation.

Methods and results: Among inhibitors specific to PKC activators, phosphatidylcholine-specific phospholipase C (PC-PLC) inhibitor D609 limited apoCIII-induced PKC alpha activation and THP-1 cell adhesion. ApoCIII increased PC-PLC activity in THP-1 cells, resulting in PKC alpha activation. Pertussis toxin (PTX) inhibited apoCIII-induced PC-PLC activation and subsequent PKC alpha activation, implicating PTX-sensitive G protein pathway. ApoCIII further activated nuclear factor-kappaB (NF-kappaB) through PKC alpha in THP-1 cells and augmented beta1-integrin expression. The NF-kappaB inhibitor peptide SN50 partially inhibited apoCIII-induced beta1-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 PKC alpha stimulation in THP-1 cells exposed to apoCIII, activating NF-kappaB, and increasing beta1-integrin. This action causes monocytic cells to adhere to endothelial cells. Furthermore, because leukocyte NF-kappaB activation contributes to inflammatory aspects of atherogenesis, apoCIII may stimulate diverse inflammatory responses through monocyte activation.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apolipoprotein C-III / physiology*
  • Bridged-Ring Compounds / pharmacology
  • Cell Adhesion / drug effects
  • Cell Adhesion / physiology
  • Cell Line
  • Endothelium, Vascular / cytology
  • Endothelium, Vascular / physiology*
  • Enzyme Activation
  • GTP-Binding Proteins / genetics
  • GTP-Binding Proteins / physiology*
  • Gene Expression Regulation
  • Humans
  • Integrin beta1 / genetics
  • Integrin beta1 / physiology
  • Monocytes / cytology
  • Monocytes / physiology*
  • NF-kappa B / genetics
  • NF-kappa B / physiology*
  • Norbornanes
  • Pertussis Toxin / pharmacology*
  • Phosphatidylinositol Diacylglycerol-Lyase / antagonists & inhibitors
  • Phosphatidylinositol Diacylglycerol-Lyase / genetics
  • Phosphatidylinositol Diacylglycerol-Lyase / physiology
  • Phosphodiesterase Inhibitors / pharmacology
  • Protein Kinase C-alpha / metabolism*
  • Thiocarbamates
  • Thiones / pharmacology

Substances

  • Apolipoprotein C-III
  • Bridged-Ring Compounds
  • Integrin beta1
  • NF-kappa B
  • Norbornanes
  • Phosphodiesterase Inhibitors
  • Thiocarbamates
  • Thiones
  • tricyclodecane-9-yl-xanthogenate
  • Pertussis Toxin
  • Protein Kinase C-alpha
  • GTP-Binding Proteins
  • Phosphatidylinositol Diacylglycerol-Lyase