A novel beta-oxa polyunsaturated fatty acid downregulates the activation of the IkappaB kinase/nuclear factor kappaB pathway, inhibits expression of endothelial cell adhesion molecules, and depresses inflammation

• Published in: Circulation research Vol. 99; no. 1; pp. 34 - 41
• Main Authors: Ferrante, Antonio, Robinson, Brenton S, Singh, Harmeet, Jersmann, Hubertus P A, Ferrante, Judith V, Huang, Zhi H, Trout, Neil A, Pitt, Michael J, Rathjen, Deborah A, Easton, Christopher J, Poulos, Alf, Prager, Rolf H, Lee, Frank S, Hii, Charles S T
• Format: Journal Article
• Language: English
• Published: United States 07.07.2006
• Subjects: Animals; Anti-Inflammatory Agents - chemistry; Anti-Inflammatory Agents - pharmacology; Arachidonate 12-Lipoxygenase - physiology; Cell Adhesion - drug effects; Cells, Cultured; Down-Regulation; Endothelial Cells - physiology; Fatty Acids, Unsaturated - chemistry; Fatty Acids, Unsaturated - metabolism; Fatty Acids, Unsaturated - pharmacology; Humans; I-kappa B Kinase - metabolism; Intercellular Adhesion Molecule-1 - metabolism; Mice; Mice, Inbred BALB C; Monocytes - physiology; Neutrophils - physiology; NF-kappa B - metabolism; Respiratory Burst - drug effects; Signal Transduction - drug effects; Tumor Necrosis Factor-alpha - pharmacology; Vascular Cell Adhesion Molecule-1 - metabolism
• ISSN: 1524-4571

Several novel polyunsaturated fatty acids (PUFAs) that contain either an oxygen or sulfur atom in the beta-position were found to exhibit more selective antiinflammatory properties than their natural PUFA counterparts. One of these, beta-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, beta-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 beta-oxa-23:4n-6 required a functional 12- but not 5-lipoxygenase or cyclooxygenases, consistent with its metabolism via the 12-lipoxygenase pathway. Whereas beta-oxa-23:4n-6 did not affect the activation of mitogen-activated protein kinases by tumor necrosis factor, activation of the IkappaB kinase/nuclear factor kappaB pathway was selectively inhibited. These novel PUFAs could form the basis for a potential new class of pharmaceuticals for treating inflammatory diseases, including atherosclerosis.