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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2007;27:219.)
© 2007 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

Apolipoprotein CIII-Induced THP-1 Cell Adhesion to Endothelial Cells Involves Pertussis Toxin-Sensitive G Protein- and Protein Kinase C-Mediated Nuclear Factor-B Activation

Akio Kawakami; Masanori Aikawa; Noriko Nitta; Masayuki Yoshida; Peter Libby; Frank M. Sacks

From the Department of Nutrition (A.K., F.M.S.), Harvard School of Public Health, and the Cardiovascular Division (M.A., P.L., F.M.S.), Brigham and Women’s Hospital, Department of Medicine, Harvard Medical School, Boston, Mass; and the Department of Medical Biochemistry (N.N., M.Y.), Graduate School of Medicine, Tokyo Medical and Dental University, Japan. Current affiliation for A.K.: Geriatrics and Vascular Medicine, Tokyo Medical and Dental University, Japan.

Correspondence to Frank M. Sacks, MD, Department of Nutrition, Harvard School of Public Health, 665 Huntington Avenue, Boston, MA 02115. E-mail fsacks{at}hsph.harvard.edu

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

Methods and Results— Among inhibitors specific to PKC activators, phosphatidylcholine-specific phospholipase C (PC-PLC) inhibitor D609 limited apoCIII-induced PKC activation and THP-1 cell adhesion. ApoCIII increased PC-PLC activity in THP-1 cells, resulting in PKC activation. Pertussis toxin (PTX) inhibited apoCIII-induced PC-PLC activation and subsequent PKC activation, implicating PTX-sensitive G protein pathway. ApoCIII further activated nuclear factor-B (NF-B) through PKC in THP-1 cells and augmented ß1-integrin expression. The NF-B inhibitor peptide SN50 partially inhibited apoCIII-induced ß1-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 stimulation in THP-1 cells exposed to apoCIII, activating NF-B, and increasing ß1-integrin. This action causes monocytic cells to adhere to endothelial cells. Furthermore, because leukocyte NF-B activation contributes to inflammatory aspects of atherogenesis, apoCIII may stimulate diverse inflammatory responses through monocyte activation.

This study showed that apoCIII alone or VLDL containing apoCIII activates PKC through the PTX-sensitive G protein pathway in human monocytic cells, leading to NF-B activation and increased ß1-integrin expression. Leukocyte NF-B activation contributes importantly to inflammatory aspects of atherogenesis. Thus, apoCIII may stimulate diverse inflammatory responses through monocyte activation.

Key Words: apolipoproteins • atherosclerosis • adhesion molecules • leukocytes • signal transduction

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