Published online before print August 7, 2006, doi: 10.1161/CIRCULATIONAHA.106.622514
(Circulation. 2006;114:681-687.)
© 2006 American Heart Association, Inc.
Vascular Medicine |
Apolipoprotein CIII Induces Expression of Vascular Cell Adhesion Molecule-1 in Vascular Endothelial Cells and Increases Adhesion of Monocytic Cells
From the Department of Nutrition, Harvard School of Public Health (A.K., F.M.S.); Center for Excellence in Vascular Biology, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School (M.A., P.L., F.M.S.); and Center for Excellence in Vascular Biology, Department of Pathology, Brigham and Women’s Hospital and Harvard Medical School (P.A., F.W.L.), Boston, Mass. Dr Kawakami is now affiliated with the Department of Geriatrics and Vascular Medicine, Tokyo Medical and Dental University, Tokyo, Japan.
Correspondence to Frank M. Sacks, MD, Nutrition Department, Harvard School of Public Health, 665 Huntington Ave, Boston, MA 02115. E-mail fsacks{at}hsph.harvard.edu
Received March 9, 2006; revision received May 22, 2006; accepted June 7, 2006.
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/cm2). ApoCIII increased EC expression of vascular cell adhesion molecule-1 (VCAM-1) protein and intercellular cell adhesion molecule-1 (ICAM-1) protein (4.9±1.5-fold and 1.4±0.5-fold versus control, respectively). Furthermore, apoCIII remarkably increased membrane-bound protein kinase C (PKC) ß in ECs, indicating activation. A selective inhibitor of PKCß 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. PKCß 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 PKCß 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 PKCß activation.
Conclusions— Our findings provide the first evidence that apoCIII increases VCAM-1 and ICAM-1 expression in ECs by activating PKCß 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.
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