TY - JOUR
T1 - 12/15-Lipoxygenase-dependent ROS production is required for diet-induced endothelial barrier dysfunction
AU - Chattopadhyay, Rima
AU - Tinnikov, Alexander
AU - Dyukova, Elena
AU - Singh, Nikhlesh K.
AU - Kotla, Sivareddy
AU - Mobley, James A.
AU - Rao, Gadiparthi N.
N1 - Publisher Copyright:
© 2015 by the American Society for Biochemistry and Molecular Biology, Inc.
PY - 2015/3/1
Y1 - 2015/3/1
N2 - To understand the mechanisms of 15(S)-HETEinduced 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. -Chattopadhyay, R., A. Tinnikov, E. Dyukova, N. K. Singh, S. Kotla, J. A. Mobley, and G. N. Rao. 12/15- Lipoxygenase-dependent ROS production is required for diet-induced endothelial barrier dysfunction. J. Lipid Res.
AB - To understand the mechanisms of 15(S)-HETEinduced 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. -Chattopadhyay, R., A. Tinnikov, E. Dyukova, N. K. Singh, S. Kotla, J. A. Mobley, and G. N. Rao. 12/15- Lipoxygenase-dependent ROS production is required for diet-induced endothelial barrier dysfunction. J. Lipid Res.
KW - 15(s)- Hydroxyeicosatetraenoic acid
KW - 15-lipoxygenase 1
KW - Reactive oxygen species
KW - Tight junction
KW - Xanthine oxidase
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UR - http://www.scopus.com/inward/citedby.url?scp=84924603360&partnerID=8YFLogxK
U2 - 10.1194/jlr.M055566
DO - 10.1194/jlr.M055566
M3 - Article
C2 - 25556764
AN - SCOPUS:84924603360
SN - 0022-2275
VL - 56
SP - 562
EP - 577
JO - Journal of lipid research
JF - Journal of lipid research
IS - 3
ER -