12/15-Lipoxygenase-dependent ROS production is required for diet-induced endothelial barrier dysfunction

Abstract

This article is available online at http://www.jlr.org surface to the circulating blood, and releases vasoactive substances involved in the regulation of vascular tone ( 1, 2 ). Besides, it selectively permits the movement of molecules into and out of the bloodstream, and this semipermeable capacity of the endothelial monolayer depends majorly on cell-to-cell connections, namely adherens junctions (AJs), tight junctions (TJs), and gap junctions ( 3, 4 ). Disruption of these junctions leads to a leaky endothelial barrier, which allows the traffi cking of leukocytes through the blood vessels into the interstitial space and initiates infl ammation ( 2, 4 ). A large body of evidence indicates that TJs of endothelium play a pivotal role in modulating its barrier permeability, and dysfunctional endothelium often manifests increased barrier permeability ( 5, 6 ). Many studies suggest that oxidative stress is one of the underlying factors in endothelial dysfunction and atherosclerosis ( 7,8 ). NADPH oxidase, a major source of reactive oxygen species (ROS) production ( 9 ), has been reported to increase EC barrier permeability ( 10, 11 ). Xanthine oxidase (XO), a purine-catabolizing enzyme, was also found as another major source of cellular ROS production ( 12 ). XO results from sulfhydryl oxidation or proteolytic conversion of xanthine dehydrogenase (XDH) ( 13,14 ). Although both XDH and XO convert hypoxanthine and xanthine to uric acid, XO preferentially converts molecular oxygen to superoxide anion and hydrogen peroxide ( 12 ). However, under the reduced state, XDH can also react with molecular oxygen and generate ROS ( 15 ). Although the physiological signifi cance of XDH conversion to XO is not clear, XO was found to be abundantly present in several tissues, including in the luminal surface of the microvascular endothelium, and is thought to be involved in the pathogenesis of various diseases such as infl ammation and Endothelium, which is constituted by a monolayer of endothelial cells (ECs), is the inner most lining of the blood vessels, provides nonplatelet adherent nonthrombotic Abstract 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

Reactive Oxygen Species (ROS) Mediate p300-dependent STAT1 Protein Interaction with Peroxisome Proliferator-activated Receptor (PPAR)-γ in CD36 Protein Expression and Foam Cell Formation

“…A large body of data suggests that oxidative stress plays a role in atherogenesis (50,51). Our results reveal that the 12/15-LO-12/15(S)-HETE axis induces ROS production both in vitro and in vivo by activating XO and/or NADPH oxidase (24,52). In addition, we have reported that 15(S)-HETE via ROS production and activation of non-receptor tyrosine kinases such as Src and Pyk2 mediates TJ protein tyrosine phosphorylation and TJ disruption causing endothelial cell dysfunction (52)(53)(54).…”

“…Our results reveal that the 12/15-LO-12/15(S)-HETE axis induces ROS production both in vitro and in vivo by activating XO and/or NADPH oxidase (24,52). In addition, we have reported that 15(S)-HETE via ROS production and activation of non-receptor tyrosine kinases such as Src and Pyk2 mediates TJ protein tyrosine phosphorylation and TJ disruption causing endothelial cell dysfunction (52)(53)(54). Many studies have reported that 15-LO mediates LDL oxidation (55,56) and 15-LO products possess the prooxidant activity (57).…”

“…Many studies have reported that 15-LO mediates LDL oxidation (55,56) and 15-LO products possess the prooxidant activity (57). Based on all these observations, it appears that 15(S)-HETE by producing ROS triggers a plethora of events, including inflammation via induction of expression of proinflammatory cytokines such as IL-6 (58) and IL-17A (59), chemokines such as MCP1 (60), endothelial cell dysfunction via phosphorylation of TJ proteins and TJ disruptions (52)(53)(54), and foam cell formation via LDL oxidation (55,56) and CD36 expression (24) may play quite an important role in atherogenesis.…”

Resolvin D1 via prevention of ROS-mediated SHP2 inactivation protects endothelial adherens junction integrity and barrier function

“…PP1 and PP2, two potent inhibitors of the Src family of PTKs [33], blocked LPS-induced tyrosine phosphorylation of α-catenin and VE-cadherin as well as their dissociation from each other (Fig. 3A).…”

“…Previously, we have shown that XO via ROS production was involved in the activation of Src and Pyk2 in 15(S)-HETE-induced endothelial TJ protein tyrosine phosphorylation, TJ disruption and its barrier dysfunction [33]. Therefore, to understand the mechanisms by which RvD1 prevents Frk-mediated tyrosine phosphorylation of α-catenin and VE-cadherin, we have studied the effect of RvD1 on LPS-induced XO activity.…”