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(Circulation Research. 2006;99:34.)
© 2006 American Heart Association, Inc.

Molecular Medicine

A Novel ß-Oxa Polyunsaturated Fatty Acid Downregulates the Activation of the IB Kinase/Nuclear Factor B Pathway, Inhibits Expression of Endothelial Cell Adhesion Molecules, and Depresses Inflammation

Antonio Ferrante, Brenton S. Robinson, Harmeet Singh, Hubertus P.A. Jersmann, Judith V. Ferrante, Zhi H. Huang, Neil A. Trout, Michael J. Pitt, Deborah A. Rathjen, Christopher J. Easton, Alf Poulos, Rolf H. Prager, Frank S. Lee, Charles S.T. Hii

From the Departments of Immunopathology (A.F., B.S.R., H.S., H.P.A.J., J.V.F., A.P., C.S.T.H.), Women’s and Children’s Hospital, University of Adelaide, South Australia; the Department of Paediatrics (A.F., H.P.A.J., C.S.T.H.), University of Adelaide, South Australia; Section of Endocrinology and Metabolism (Z.H.H.), Rush Presbyterian Hospital-St Luke’s Medical Center, Chicago, Ill; School of Pharmaceutical, Molecular and Biomedical Sciences (A.F.), University of South Australia; Department of Chemistry (N.A.T., R.H.P.), Flinders University, Bedford Park, South Australia; Therapeutic Goods and Administration (M.J.P.), Symonston, Australia; Bionomics (D.A.R.), Thebarton, South Australia; Research School of Chemistry (C.J.E.), Australian National University, Canberra, Australia; and Department of Pathology and Laboratory Medicine (F.S.L.), University of Pennsylvania School of Medicine, Philadelphia.

Correspondence to Prof A. Ferrante, Department of Immunopathology, Women’s and Children’s Hospital, Adelaide, SA 5006, Australia. E-mail antonio.ferrante{at}adelaide.edu.au

Several novel polyunsaturated fatty acids (PUFAs) that contain either an oxygen or sulfur atom in the ß-position were found to exhibit more selective antiinflammatory properties than their natural PUFA counterparts. One of these, ß-oxa-23:4n-6, unlike natural PUFAs, lacked ability to stimulate oxygen radical production in neutrophils but caused marked inhibition of agonist-induced upregulation of leukocyte adhesion to cultured human umbilical vein endothelial cells (HUVEC) and E-selectin, intercellular adhesion molecule-1, and vascular cell adhesion molecule-1 expression. In addition, ß-oxa-23:4n-6 inhibited acute and chronic inflammatory responses in mice as well as the upregulation of adhesion molecule expression in arterial endothelium. This action of ß-oxa-23:4n-6 required a functional 12- but not 5-lipoxygenase or cyclooxygenases, consistent with its metabolism via the 12-lipoxygenase pathway. Whereas ß-oxa-23:4n-6 did not affect the activation of mitogen-activated protein kinases by tumor necrosis factor, activation of the IB kinase/nuclear factor B pathway was selectively inhibited. These novel PUFAs could form the basis for a potential new class of pharmaceuticals for treating inflammatory diseases, including atherosclerosis.

Key Words: Long chain fatty acids • endothelial cells • adhesion molecules • lipoxygenase • NF-B

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