Published online before print June 8, 2006, doi: 10.1161/01.RES.0000231292.66084.cd
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Submitted on October 5, 2005
Revised on May 17, 2006
Accepted on May 26, 2006
A Novel 
-Oxa Polyunsaturated Fatty Acid Downregulates the Activation of the I
B Kinase/Nuclear Factor B Pathway, Inhibits Expression of Endothelial Cell Adhesion Molecules, and Depresses Inflammation
Antonio Ferrante *;
From the Departments of Immunopathology and Paediatrics (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; 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.
* To whom correspondence should be addressed. E-mail: antonio.ferrante{at}adelaide.edu.au.
Several novel polyunsaturated fatty acids (PUFAs) that contain either an oxygen or sulfur atom in the 
-position were found to exhibit more selective antiinflammatory properties than their natural PUFA counterparts. One of these, -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, -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 -oxa-23:4n-6 required a functional 12- but not 5-lipoxygenase or cyclooxygenases, consistent with its metabolism via the 12-lipoxygenase pathway. Whereas -oxa-23:4n-6 did not affect the activation of mitogen-activated protein kinases by tumor necrosis factor, activation of the I
B 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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