title: Albumin-derived advanced glycation end-products trigger the disruption of the vascular endothelial cadherin complex in cultured human and murine endothelial cells.
abstract: Endothelial cell (EC) junctions regulate in large part the integrity and barrier function of the vascular endothelium. Advanced glycation end-products (AGEs), the irreversibly formed reactive derivatives of non-enzymic glucose-protein condensation reactions, are strongly implicated in endothelial dysfunction that distinguishes diabetes- and aging-associated vascular complications. The aim of the present study was to determine whether AGEs affect EC lateral junction proteins, with particular regard to the vascular endothelial cadherin (VE-cadherin) complex. Our results indicate that AGE-modified BSA (AGE-BSA), a prototype of advanced glycated proteins, disrupts the VE-cadherin complex when administered to ECs. AGE-BSA, but not unmodified BSA, was found to induce decreases in the levels of VE-cadherin, beta-catenin and gamma-catenin in the complex and in total cell extracts, as well as a marked reduction in the amount of VE-cadherin present at the cell surface. In contrast, the level of platelet endothelial cell adhesion molecule-1 (PECAM-1), which is located at lateral junctions, was not altered. Supplementation of the cellular antioxidative defences abolished these effects. Finally, the loss of components of the VE-cadherin complex was correlated with increases in vascular permeability and in EC migration. These findings suggest that some of the AGE-induced biological effects on the endothelium could be mediated, at least in part, by the weakening of intercellular contacts caused by decreases in the amount of VE-cadherin present.
authors.affiliation: Laboratorio de Farmacología, Centro de Química Farmacéutica, Apartado Postal 6990, La Habana, Cuba. otero@marionegri.it
authors.forename: K
authors.initials: K
authors.lastname: Otero
authors.forename: F
authors.initials: F
authors.lastname: Martínez
authors.forename: A
authors.initials: A
authors.lastname: Beltrán
authors.forename: D
authors.initials: D
authors.lastname: González
authors.forename: B
authors.initials: B
authors.lastname: Herrera
authors.forename: G
authors.initials: G
authors.lastname: Quintero
authors.forename: R
authors.initials: R
authors.lastname: Delgado
authors.forename: A
authors.initials: A
authors.lastname: Rojas
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology; D000418:Albumins / Q000378:metabolism*; D000818:Animals; D015820:Cadherins / Q000378:metabolism*; D002417:Cattle; D002478:Cells, Cultured; D003598:Cytoskeletal Proteins / Q000378:metabolism; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D016166:Free Radical Scavengers / Q000494:pharmacology; D017127:Glycation End Products, Advanced / Q000378:metabolism* / Q000494:pharmacology*; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D012710:Serum Albumin, Bovine / Q000494:pharmacology*; D015534:Trans-Activators; D051176:beta Catenin
chemical_list: D000418:Albumins; C495270:CTNNB1 protein, human; C495267:CTNNB1 protein, mouse; D015820:Cadherins; D003598:Cytoskeletal Proteins; D016166:Free Radical Scavengers; D017127:Glycation End Products, Advanced; D015534:Trans-Activators; C081628:advanced glycation end products-bovine serum albumin; D051176:beta Catenin; D012710:Serum Albumin, Bovine; D000111:Acetylcysteine