title: 12/15-Lipoxygenase-dependent ROS production is required for diet-induced endothelial barrier dysfunction.
abstract: To understand the mechanisms of 15(S)-HETE-induced endothelial cell (EC) barrier dysfunction, we examined the role of xanthine oxidase (XO). 15(S)-HETE induced junction adhesion molecule A (JamA) phosphorylation on Y164, Y218, and Y280 involving XO-mediated reactive oxygen species production and Src and Pyk2 activation, resulting in its dissociation from occludin, thereby causing tight junction (TJ) disruption, increased vascular permeability, and enhanced leukocyte and monocyte transmigration in vitro using EC monolayer and ex vivo using arteries as models. The phosphorylation of JamA on Y164, Y218, and Y280 appears to be critical for its role in 15(S)-HETE-induced EC barrier dysfunction, as mutation of any one of these amino acid residues prevented its dissociation from occludin and restored TJ integrity and barrier function. In response to high-fat diet (HFD) feeding, WT, but not 12/15-lipoxygenase (LO)(-/-), mice showed enhanced XO expression and its activity in the artery, which was correlated with increased aortic TJ disruption and barrier permeability with enhanced leukocyte adhesion and these responses were inhibited by allopurinol. These observations provide novel insights on the role of XO in 12/15-LO-induced JamA tyrosine phosphorylation and TJ disruption leading to increased vascular permeability in response to HFD.
authors.affiliation: Department of Physiology, University of Tennessee Health Science Center, Memphis, TN 38138.
authors.forename: Rima
authors.initials: R
authors.lastname: Chattopadhyay
authors.affiliation: Department of Physiology, University of Tennessee Health Science Center, Memphis, TN 38138.
authors.forename: Alexander
authors.initials: A
authors.lastname: Tinnikov
authors.affiliation: Department of Physiology, University of Tennessee Health Science Center, Memphis, TN 38138.
authors.forename: Elena
authors.initials: E
authors.lastname: Dyukova
authors.affiliation: Department of Physiology, University of Tennessee Health Science Center, Memphis, TN 38138.
authors.forename: Nikhlesh K
authors.initials: NK
authors.lastname: Singh
authors.affiliation: Department of Physiology, University of Tennessee Health Science Center, Memphis, TN 38138.
authors.forename: Sivareddy
authors.initials: S
authors.lastname: Kotla
authors.affiliation: Department of Surgery, University of Alabama at Birmingham, Birmingham, AL 35291.
authors.forename: James A
authors.initials: JA
authors.lastname: Mobley
authors.affiliation: Department of Physiology, University of Tennessee Health Science Center, Memphis, TN 38138. Electronic address: rgadipar@uthsc.edu.
authors.forename: Gadiparthi N
authors.initials: GN
authors.lastname: Rao
mesh_terms: D000818:Animals; D001011:Aorta / Q000378:metabolism / Q000473:pathology; D001092:Arachidonate 12-Lipoxygenase / Q000235:genetics / Q000378:metabolism*; D001093:Arachidonate 15-Lipoxygenase / Q000235:genetics / Q000378:metabolism*; D002199:Capillary Permeability / Q000187:drug effects* / Q000235:genetics; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism; D004041:Dietary Fats / Q000009:adverse effects* / Q000494:pharmacology; D015118:Eicosapentaenoic Acid / Q000031:analogs & derivatives / Q000235:genetics / Q000378:metabolism; D004730:Endothelium, Vascular / Q000201:enzymology* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D017382:Reactive Oxygen Species / Q000378:metabolism*; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism; D019108:Tight Junctions / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D014969:Xanthine Oxidase / Q000235:genetics / Q000378:metabolism
chemical_list: C475064:12-15-lipoxygenase; D015815:Cell Adhesion Molecules; D004041:Dietary Fats; C498686:F11r protein, mouse; D017382:Reactive Oxygen Species; D011956:Receptors, Cell Surface; C059164:15-hydroxy-5,8,11,13,17-eicosapentaenoic acid; D015118:Eicosapentaenoic Acid; D001092:Arachidonate 12-Lipoxygenase; D001093:Arachidonate 15-Lipoxygenase; D014969:Xanthine Oxidase
keywords: 15(S)-hydroxyeicosatetraenoic acid; 15-lipoxygenase 1; reactive oxygen species; tight junction; xanthine oxidase