on October 23, 2008
Published online before print October 23, 2008, doi: 10.1161/ATVBAHA.108.171736
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Submitted on June 6, 2008
Accepted on September 24, 2008
In Vivo and In Vitro Inhibition of Monocyte Adhesion to Endothelial Cells and Endothelial Adhesion Molecules by Eicosapentaenoic Acid
Hideto Yamada ;
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.
* To whom correspondence should be addressed. 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.
Key words: adhesion molecules • endothelial cells • EPA • monocytes • TLR4