Published Online
on August 7, 2006

A more recent version of this article appeared on August 15, 2006

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Submitted on March 9, 2006
Revised on May 22, 2006
Accepted on June 7, 2006

Apolipoprotein CIII Induces Expression of Vascular Cell Adhesion Molecule-1 in Vascular Endothelial Cells and Increases Adhesion of Monocytic Cells

Akio Kawakami MD, Masanori Aikawa MD, PhD, Pilar Alcaide PhD, Francis W. Luscinskas PhD, Peter Libby MD, and Frank M. Sacks MD^*

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.

^* To whom correspondence should be addressed. E-mail: fsacks{at}hsph.harvard.edu.

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) in ECs, indicating activation. A selective inhibitor of PKC 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. PKC 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 PKC 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 PKC activation.

Conclusions--Our findings provide the first evidence that apoCIII increases VCAM-1 and ICAM-1 expression in ECs by activating PKC 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.

Key words: apolipoproteins • atherosclerosis • cell adhesion molecules • endothelial cells

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