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Prepublished online as a Blood First Edition Paper on May 17, 2002; DOI 10.1182/blood-2002-01-0316.
Submitted February 1, 2002
Accepted April 8, 2002
Oxidized omega-3 fatty acids in fish oil inhibit leukocyte-endothelial interactions through activation of PPAR
Sanjeev Sethi, Ouliana Ziouzenkova, Heyu Ni, Denisa D Wagner, Jorge Plutzky, and Tanya N Mayadas*
Vascular Research Division, Department of Pathology, Brigham and Women's Hospital/Harvard Medical School, Boston, MA, USA
Division of Vascular Medicine, Department of Medicine, Brigham and Women's Hospital/Harvard Medical School, Boston, MA, USA
Department of Pathology, Center for Blood Research/Harvard Medical School, Boston, MA, USA
* Corresponding author; email: tmayadas{at}rics.bwh.harvard.edu.
Omega-3 fatty acids which are abundant in fish oil improve the prognosis of several chronic inflammatory diseases although the mechanism for such effects remain unclear. These fatty acids, such as eicosapentanoic acid (EPA), are highly polyunsaturated and readily undergo oxidation. We show that oxidized, but not native unoxidized EPA significantly inhibited human neutrophil and monocyte adhesion to endothelial cells in vitro by inhibiting endothelial adhesion receptor expression. In transcriptional co-activation assays, oxidized EPA potently activated the peroxisome proliferator-activated receptor (PPAR), a member of the nuclear receptor family. In vivo, oxidized, but not native, EPA markedly reduced leukocyte rolling and adhesion to venular endothelium of LPS-treated mice. This occurred via a PPAR-dependent mechanism since oxidized EPA had no such effect in LPS-treated PPAR-deficient mice. Therefore, the beneficial effects of omega-3 fatty acids may be explained by a PPAR-mediated anti-inflammatory effect of oxidized EPA.
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