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Oxidized phospholipids mediate occludin expression and phosphorylation in vascular endothelial cells

Lucas DeMaio,¹ Mahsa Rouhanizadeh,¹ Srinivasa Reddy,³ Alex Sevanian,^2, Juliana Hwang,² and Tzung K. Hsiai^1,2

¹Department of Biomedical Engineering and Division of Cardiovascular Medicine, ²Division of Nephrology, Department of Molecular Pharmacology and Toxicology, University of Southern California; and ³Departments of Medicine and Medical Molecular Pharmacology, School of Medicine, University of California, Los Angeles, California

Submitted 26 May 2005 ; accepted in final form 31 August 2005

Oxidized L--1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphorylcholine (OxPAPC), a component of minimally modified LDL, induces production of proinflammatory cytokines and development of atherosclerotic lesions. We tested the hypothesis that OxPAPC alters expression, phosphorylation, and localization of tight junction (TJ) proteins, particularly occludin, a transmembrane TJ protein. OxPAPC reduced total occludin protein and increased occludin phosphorylation dose dependently (10–50 µg/ml) and time dependently in bovine aortic endothelial cells. OxPAPC decreased occludin mRNA and reduced the immunoreactivity of zonula occludens-1 at the cell-cell contacts. Furthermore, OxPAPC increased the diffusive flux of 10-kDa dextran in a dose-dependent manner. O₂^–· production by bovine aortic endothelial cells increased nearly twofold after exposure to OxPAPC. Also, enzymatic generation of O₂^–· by xanthine oxidase-lumazine and H₂O₂ by glucose oxidase-glucose increased occludin phosphorylation, implicating reactive oxygen species as modulators of the OxPAPC effects on occludin phosphorylation. Superoxide dismutase and/or catalase blocked the effects of OxPAPC on occludin protein content and phosphorylation, occludin mRNA, zonula occludens-1 immunoreactivity, and diffusive flux of 10-kDa dextran. These findings suggest that changes in TJ proteins are potential mechanisms by which OxPAPC compromises the barrier properties of the vascular endothelium. OxPAPC-induced disruption of TJs, which likely facilitates transmigration of LDL and inflammatory cells into the subendothelial layers, may be mediated by reactive oxygen species.

oxidized L--1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphorylcholine; reactive oxygen species

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