Albumin-derived advanced glycation end-products trigger the disruption of the vascular endothelial cadherin complex in cultured human and murine endothelial cells.
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.
Otero
K
K
Laboratorio de Farmacología, Centro de Química Farmacéutica, Apartado Postal 6990, La Habana, Cuba. otero@marionegri.it
Martínez
F
F
Beltrán
A
A
González
D
D
Herrera
B
B
Quintero
G
G
Delgado
R
R
Rojas
A
A
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
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