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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2008;28:2173.)
© 2008 American Heart Association, Inc.

Integrative Physiology/Experimental Medicine

In Vivo and In Vitro Inhibition of Monocyte Adhesion to Endothelial Cells and Endothelial Adhesion Molecules by Eicosapentaenoic Acid

Hideto Yamada; Masayuki Yoshida; Yasutaka Nakano; Takayoshi Suganami; Noriko Satoh; Tomoya Mita; Kosuke Azuma; Michiko Itoh; Yukio Yamamoto; Yasutomi Kamei; Minoru Horie; Hirotaka Watada; Yoshihiro Ogawa

From the Department of Molecular Medicine and Metabolism (H.Y., T.S., M.I., Y.K., Y.O.), Medical Top Track (MTT) Program, Medical Research Institute (Y.Y.), Global Center of Excellence Program, International Research Center for Molecular Science in Tooth and Bone Diseases (Y.O.); and Bioethics Research Center (M.Y.), Tokyo Medical and Dental University; Cardiovascular and Respiratory Medicine (H.Y., Y.N., M.H.), Shiga University of Medical Science, Otsu; Clinical Research Institute for Endocrine Metabolic Disease (N.S.), National Hospital Organization, Kyoto Medical Center, Kyoto; and the Department of Medicine, Metabolism, and Endocrinology (T.M., K.A., H.W.), Juntendo University School of Medicine, Tokyo, Japan.

Correspondence to Yoshihiro Ogawa, Department of Molecular Medicine and Metabolism, Medical Research Institute, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510. E-mail ogawa.mmm{at}mri.tmd.ac.jp

Objective— A large-scale, prospective, randomized clinical trial has recently revealed that the addition of highly purified eicosapentaenoic acid (EPA) to low-dose statin therapy significantly reduces the incidence of major coronary events. Here we investigated in vivo and in vitro effect of EPA on monocyte adhesion to endothelial cells and adhesion molecules.

Methods and Results— A new en face immunohistochemistry of endothelial surface in combination with confocal microscopy revealed marked reduction of lipopolysaccharide (LPS)-induced monocyte adhesion to the aortic endothelium in parallel with the suppression of vascular cell adhesion molecule 1 (VCAM-1) and nuclear translocation of nuclear factor-B p65 in EPA-treated mice relative to vehicle-treated groups. In an in vitro adhesion assay system under physiological flow conditions, EPA inhibited LPS-induced monocyte adhesion and endothelial adhesion molecules. We found significant decrease in plasma concentrations of soluble intercellular adhesion molecule 1 (sICAM-1) and sVCAM-1 in patients with the metabolic syndrome after a 3-month administration of highly purified EPA (1.8 g daily). Multivariate regression analysis revealed that EPA administration is the only independent determinant of sICAM-1 and sVCAM-1.

Conclusions— This study provides evidence that EPA inhibits monocyte adhesion to endothelial cells in parallel with the suppression of endothelial adhesion molecules in vivo and in vitro.

This study provides evidence that EPA inhibits monocyte adhesion to endothelial cells in parallel with the suppression of endothelial adhesion molecules and nuclear translocation of NF-B p65 in vivo and in vitro, thereby facilitating the better understanding of the molecular mechanism underlying the antiatherogenic effect of EPA.

Key Words: adhesion molecules • endothelial cells • EPA • monocytes • TLR4