title: 12/15-Lipoxygenase mediates high-fat diet-induced endothelial tight junction disruption and monocyte transmigration: a new role for 15(S)-hydroxyeicosatetraenoic acid in endothelial cell dysfunction.
abstract: A convincing body of evidence suggests that 12/15-lipoxygenase (12/15-LO) plays a role in atherosclerosis. However, the mechanisms of its involvement in the pathogenesis of this disease are not clear. Therefore, the purpose of this study is to understand the mechanisms by which 12/15-LO mediates endothelial dysfunction. 15(S)-Hydroxyeicosatetraenoic acid (15(S)-HETE), the major 12/15-LO metabolite of arachidonic acid (AA), induced endothelial barrier permeability via Src and Pyk2-dependent zonula occluden (ZO)-2 tyrosine phosphorylation and its dissociation from the tight junction complexes. 15(S)-HETE also stimulated macrophage adhesion to the endothelial monolayer in Src and Pyk2-dependent manner. Ex vivo studies revealed that exposure of arteries from WT mice to AA or 15(S)-HETE led to Src-Pyk2-dependent ZO-2 tyrosine phosphorylation, tight junction disruption, and macrophage adhesion, whereas the arteries from 12/15-LO knock-out mice are protected from these effects of AA. Feeding WT mice with a high-fat diet induced the expression of 12/15-LO in the arteries leading to tight junction disruption and macrophage adhesion and deletion of the 12/15-LO gene disallowed these effects. Thus, the findings of this study provide the first evidence of the role of 12/15-LO and its AA metabolite, 15(S)-HETE, in high-fat diet-induced endothelial tight junction disruption and macrophage adhesion, the crucial events underlying the pathogenesis of atherosclerosis.
authors.affiliation: Department of Physiology, University of Tennessee Health Science Center, Memphis, Tennessee 38163, USA.
authors.forename: Venkatesh
authors.initials: V
authors.lastname: Kundumani-Sridharan
authors.forename: Elena
authors.initials: E
authors.lastname: Dyukova
authors.forename: Dale E
authors.initials: DE
authors.lastname: Hansen
authors.forename: Gadiparthi N
authors.initials: GN
authors.lastname: Rao
mesh_terms: D000818:Animals; D001092:Arachidonate 12-Lipoxygenase / Q000235:genetics / Q000378:metabolism*; D001093:Arachidonate 15-Lipoxygenase / Q000235:genetics / Q000378:metabolism*; D016718:Arachidonic Acid / Q000235:genetics / Q000378:metabolism; D001158:Arteries / Q000378:metabolism / Q000473:pathology; D050197:Atherosclerosis / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D002448:Cell Adhesion / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D004041:Dietary Fats / Q000009:adverse effects* / Q000494:pharmacology; D061307:Human Umbilical Vein Endothelial Cells / Q000201:enzymology* / Q000473:pathology; D006801:Humans; D006893:Hydroxyeicosatetraenoic Acids / Q000235:genetics / Q000378:metabolism; D008264:Macrophages / Q000201:enzymology / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D019108:Tight Junctions / Q000378:metabolism* / Q000473:pathology; D062827:Zonula Occludens-2 Protein / Q000235:genetics / Q000378:metabolism
chemical_list: C475064:12-15-lipoxygenase; D004041:Dietary Fats; D006893:Hydroxyeicosatetraenoic Acids; C569046:TJP2 protein, human; C569047:Tjp2 protein, mouse; D062827:Zonula Occludens-2 Protein; D016718:Arachidonic Acid; D001092:Arachidonate 12-Lipoxygenase; D001093:Arachidonate 15-Lipoxygenase
keywords: Endothelial Cell; Lipoxygenase Pathway; Signal Transduction; Tight Junctions; Vascular Biology