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12/15‐Lipoxygenase‐Dependent ROS Production Is Required For Diet‐Induced Endothelial Barrier Dysfunction
Author(s) -
Chattopadhyay Rima,
Tinnikov Alexander,
Dyukova Elena,
Singh Nikhlesh,
Kotla Sivareddy,
Mobley James,
Rao Gadiparthi
Publication year - 2015
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.29.1_supplement.715.6
Subject(s) - occludin , tyrosine phosphorylation , phosphorylation , chemistry , vascular permeability , tight junction , endothelium , microbiology and biotechnology , barrier function , endothelial dysfunction , proto oncogene tyrosine protein kinase src , nadph oxidase , endothelial stem cell , biochemistry , medicine , endocrinology , reactive oxygen species , biology , in vitro
To understand the mechanisms of 15(S)‐hydroxyeicosatetraenoic acid (15(S)‐HETE)‐induced endothelial cell (EC) barrier dysfunction, we examined the role of xanthine oxidase (XO). 15(S)‐HETE induced JamA phosphorylation on Y164, Y218 and Y280 involving XO‐mediated ROS production and Src and Pyk2 activation, resulting in its dissociation from occludin, thereby causing tight junction 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 appear 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‐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.