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
Authors: Gadiparthi N Rao
Venkatesh Kundumani-Sridharan
Elena Dyukova
Dale E Hansen 3rd
Journal: Journal of Biological Chemistry (2013)
Discipline: BIOLOGY & BIOCHEMISTRY
Keywords: Endothelial Cell; Lipoxygenase Pathway; Signal Transduction; Tight Junctions; Vascular Biology.
Affiliations: Department of Physiology, University of Tennessee Health Science Center, Memphis, Tennessee 38163, USA.

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. 

Retracted: No

PubPeer comments:
 image duplication, stretched ![file] Disclaimer: These potential image duplications have been detected automatically using ImageTwin http: dx.doi.org 10.1145 3019612.3019875 Although results have been curated, the automatic algorithm may have generated false positive results and cannot take into account all scientific explanations for apparent duplications like stripped and reprobed blots, time series, serial sections and reused controls. , 
 Figure 25, same image for control and Glibenclamide (10 mg kg) treatment (blue boxes). ![file] , 
 Figure 18, several images have been published a year later in [*Kumar et al. 2014 BMC Compl. Altern. Med.*](http: pubpeer.com publications EA12876090A05D7D20EC3A74A7502E) by the same group, where the compound analyzed is different. Please note that this group has published [several papers](http: pubpeer.com search?q=Danish+Ahmed) by reusing same images over and over throughout several years. ![file] , 
 Figure 24 and 25, several images were published the same year later in [*Kumar et al. 2013 BMC Compl. Altern. Med. 10.1186 1472-6882-13-273*](http: pubpeer.com publications 26665E7D8B2E873C329648C9FF7A32) by the same group, where the compound analyzed was different. There are many more images in this article that were published in several other papers years later. I ll leave the burden to spot and post them all to the intrepid soul willing to accomplish this Herculean mission. ![file] ,