title: Glycated LDL increase VCAM-1 expression and secretion in endothelial cells and promote monocyte adhesion through mechanisms involving endoplasmic reticulum stress.
abstract: Type 2 Diabetes Mellitus is a worldwide epidemic, and its atherosclerotic complications produce morbidity and mortality in affected patients. It is known that the vascular cell adhesion molecule-1 (VCAM-1) levels are increased in the sera of diabetic patients. Our aim was to investigate the impact of the endoplasmic reticulum stress (ERS) in VCAM-1 expression and secretion in human endothelial cells (HEC) exposed to glycated low-density lipoproteins (gLDL). The results showed that 24 h incubation of HEC with gLDL induces (i) stimulation of VCAM-1 expression and secretion, determining increased monocyte adhesion to HEC; (ii) RAGE up-regulation and free cholesterol loading; (iii) ERS activation (increased eIF2α phosphorylation and CHOP mRNA levels, and decreased GRP78 protein expression); and (iv) oxidative stress [increased levels of reactive oxygen species (ROS) and glutamate cysteine ligase catalytic unit gene expression]. Treatment of gLDL-exposed HEC with ERS inhibitors, salubrinal (Sal) and sodium phenylbutyrate (PBA), decreased intracellular ROS. Incubation of gLDL-exposed cells with the anti-oxidant N-acetyl-cysteine (NAC) reduced ERS, revealed by decreased eIF2α phosphorylation and CHOP gene expression and increased GRP78 expression, thus validating the interconnection between ERS and oxidative stress. Sal, PBA, NAC and inhibitors of p38 MAP kinase and NF-kB induced the decrease of VCAM-1 expression and of the ensuing monocyte adhesion induced by gLDL. In conclusion, in HEC, gLDL stimulate the expression of cellular VCAM-1, the secretion of soluble VCAM-1, and the adhesion of monocytes through mechanisms involving p38 MAP kinase and NF-kB signalling pathways activated by RAGE, ERS and oxidative stress, thus contributing to diabetic atherosclerosis.
authors.affiliation: Lipidomics Department, Institute of Cellular Biology and Pathology "Nicolae Simionescu" of the Romanian Academy, 8.B.P Hasdeu Street, 050568, Bucharest, Romania.
authors.forename: Laura
authors.initials: L
authors.lastname: Toma
authors.affiliation: Lipidomics Department, Institute of Cellular Biology and Pathology "Nicolae Simionescu" of the Romanian Academy, 8.B.P Hasdeu Street, 050568, Bucharest, Romania.
authors.forename: Gabriela M
authors.initials: GM
authors.lastname: Sanda
authors.affiliation: Lipidomics Department, Institute of Cellular Biology and Pathology "Nicolae Simionescu" of the Romanian Academy, 8.B.P Hasdeu Street, 050568, Bucharest, Romania.|Faculty of Biotechnology, University of Agronomical Sciences and Veterinary Medicine, Bucharest, Romania.
authors.forename: Mariana
authors.initials: M
authors.lastname: Deleanu
authors.affiliation: Lipidomics Department, Institute of Cellular Biology and Pathology "Nicolae Simionescu" of the Romanian Academy, 8.B.P Hasdeu Street, 050568, Bucharest, Romania.
authors.forename: Camelia S
authors.initials: CS
authors.lastname: Stancu
authors.affiliation: Lipidomics Department, Institute of Cellular Biology and Pathology "Nicolae Simionescu" of the Romanian Academy, 8.B.P Hasdeu Street, 050568, Bucharest, Romania. anca.sima@icbp.ro.
authors.forename: Anca V
authors.initials: AV
authors.lastname: Sima
mesh_terms: D002448:Cell Adhesion / Q000187:drug effects; D002460:Cell Line; D000091342:Endoplasmic Reticulum Chaperone BiP; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D042783:Endothelial Cells / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects*; D017127:Glycation End Products, Advanced; D006801:Humans; D008077:Lipoproteins, LDL / Q000378:metabolism / Q000494:pharmacology*; D009000:Monocytes / Q000378:metabolism*; D019010:Vascular Cell Adhesion Molecule-1 / Q000096:biosynthesis*; D000093844:Glycated Proteins
chemical_list: D000091342:Endoplasmic Reticulum Chaperone BiP; D017127:Glycation End Products, Advanced; D008077:Lipoproteins, LDL; D019010:Vascular Cell Adhesion Molecule-1; C000717247:HSPA5 protein, human; C031797:glycated lipoproteins, LDL; D000093844:Glycated Proteins
keywords: Endoplasmic reticulum stress; Endothelial cell; Glycated LDL; Oxidative stress; RAGE; VCAM-1