title: Epoxygenated Fatty Acids Inhibit Retinal Vascular Inflammation.
abstract: The objective of the present study was to assess the effect of elevating epoxygenated fatty acids on retinal vascular inflammation. To stimulate inflammation we utilized TNFα, a potent pro-inflammatory mediator that is elevated in the serum and vitreous of diabetic patients. In TNFα-stimulated primary human retinal microvascular endothelial cells, total levels of epoxyeicosatrienoic acids (EETs), but not epoxydocosapentaenoic acids (EDPs), were significantly decreased. Exogenous addition of 11,12-EET or 19,20-EDP when combined with 12-(3-adamantane-1-yl-ureido)-dodecanoic acid (AUDA), an inhibitor of epoxide hydrolysis, inhibited VCAM-1 and ICAM-1 expression and protein levels; conversely the diol product of 19,20-EDP hydrolysis, 19,20-DHDP, induced VCAM1 and ICAM1 expression. 11,12-EET and 19,20-EDP also inhibited leukocyte adherence to human retinal microvascular endothelial cell monolayers and leukostasis in an acute mouse model of retinal inflammation. Our results indicate that this inhibition may be mediated through an indirect effect on NFκB activation. This is the first study demonstrating a direct comparison of EET and EDP on vascular inflammatory endpoints, and we have confirmed a comparable efficacy from each isomer, suggesting a similar mechanism of action. Taken together, these data establish that epoxygenated fatty acid elevation will inhibit early pathology related to TNFα-induced inflammation in retinal vascular diseases.
authors.affiliation: Vanderbilt University, Department of Molecular Physiology and Biophysics, Nashville, TN, USA.
authors.forename: Megan E
authors.initials: ME
authors.lastname: Capozzi
authors.affiliation: Vanderbilt University Medical Center, Department of Ophthalmology and Visual Sciences, Nashville, TN, USA.
authors.forename: Sandra S
authors.initials: SS
authors.lastname: Hammer
authors.affiliation: Vanderbilt University Medical Center, Department of Ophthalmology and Visual Sciences, Nashville, TN, USA.
authors.forename: Gary W
authors.initials: GW
authors.lastname: McCollum
authors.affiliation: Vanderbilt University, Department of Molecular Physiology and Biophysics, Nashville, TN, USA.|Vanderbilt University Medical Center, Department of Ophthalmology and Visual Sciences, Nashville, TN, USA.
authors.forename: John S
authors.initials: JS
authors.lastname: Penn
mesh_terms: D015126:8,11,14-Eicosatrienoic Acid / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D000218:Adamantane / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D002478:Cells, Cultured; D004195:Disease Models, Animal; D015536:Down-Regulation; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D004852:Epoxy Compounds / Q000008:administration & dosage* / Q000494:pharmacology; D005231:Fatty Acids, Unsaturated / Q000008:administration & dosage* / Q000494:pharmacology; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism; D007850:Lauric Acids / Q000008:administration & dosage / Q000494:pharmacology; D008297:Male; D051379:Mice; D031300:Retinal Vasculitis / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism; D012171:Retinal Vessels / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000009:adverse effects*; D019010:Vascular Cell Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism
chemical_list: C504897:12-(3-adamantan-1-ylureido)dodecanoic acid; D004852:Epoxy Compounds; D005231:Fatty Acids, Unsaturated; D007850:Lauric Acids; D014409:Tumor Necrosis Factor-alpha; D019010:Vascular Cell Adhesion Molecule-1; D018799:Intercellular Adhesion Molecule-1; C046783:11,12-epoxy-5,8,14-eicosatrienoic acid; D015126:8,11,14-Eicosatrienoic Acid; C026219:docosapentaenoic acid; D000218:Adamantane