title: Modified low density lipoprotein and its constituents augment cytokine-activated vascular cell adhesion molecule-1 gene expression in human vascular endothelial cells.
abstract: Early features in the pathogenesis of atherosclerosis include accumulation of oxidized LDL (oxLDL) and endothelial expression of the vascular adhesion molecule VCAM-1. Because antioxidants inhibit endothelial VCAM-1 expression, we tested the hypothesis that oxLDL functions as a prooxidant signal in atherogenesis to augment VCAM-1 activation by inflammatory signals. Cultured human aortic endothelial cells (HAECs) or human umbilical vein endothelial cells (HUVECs) were incubated with unmodified LDL, oxLDL, or glycated LDL for 48 h. No change in VCAM-1, intercellular cell adhesion molecule-1 (ICAM-1), or E-selectin expression from control was observed by ELISA. However, dose-response and time course studies demonstrated that oxLDL enhanced VCAM-1 expression induced by the cytokin tumor necrosis factor alpha (TNF alpha) 63% in HAECs and 45% in HUVECs over unmodified LDL or control. Using flow cytometry analysis, oxLDL augmented TNF alpha-induced VCAM-1 expression in a uniform HAEC population. oxLDL had no effect on E-selection induction. oxLDL augmented TNF alpha-induced ICAM-1 expression 44% in HAECs but not in HUVECs. Glycated LDL augmented TNF alpha-induced VCAM-1 expression 35% in HAECs but not HUVECs. Similar results were obtained with 13-HPODE or lysophosphatidylcholine, significant components of oxLDL. 13-HPODE augmented TNF alpha-induced mRNA accumulation and transcriptional activation of VCAM-1 in HAECs. These results suggest that as long-term regulatory signals, specific oxidized fatty acid and phospholipid components of oxLDL augment the ability of vascular endothelial cells to express cytokine-mediated VCAM-1. These studies link oxidant signals conferred by oxLDL to oxidation-sensitive regulatory mechanisms controlling the expression of endothelial cell adhesion molecules involved in early atherosclerosis.
authors.affiliation: Department of Medicine, Emory University School of Medicine, Atlanta, Georgia 30322.
authors.forename: B V
authors.initials: BV
authors.lastname: Khan
authors.forename: S S
authors.initials: SS
authors.lastname: Parthasarathy
authors.forename: R W
authors.initials: RW
authors.lastname: Alexander
authors.forename: R M
authors.initials: RM
authors.lastname: Medford
mesh_terms: D001011:Aorta / Q000166:cytology; D015815:Cell Adhesion Molecules / Q000096:biosynthesis* / Q000235:genetics; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects*; D005786:Gene Expression Regulation; D006801:Humans; D008041:Linoleic Acids / Q000494:pharmacology; D008054:Lipid Peroxides / Q000494:pharmacology; D008077:Lipoproteins, LDL / Q000737:chemistry / Q000494:pharmacology*; D008244:Lysophosphatidylcholines / Q000494:pharmacology; D010084:Oxidation-Reduction; D010743:Phospholipids / Q000494:pharmacology; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D014471:Umbilical Veins / Q000166:cytology; D019010:Vascular Cell Adhesion Molecule-1
chemical_list: D015815:Cell Adhesion Molecules; D008041:Linoleic Acids; D008054:Lipid Peroxides; D008077:Lipoproteins, LDL; D008244:Lysophosphatidylcholines; D010743:Phospholipids; D014409:Tumor Necrosis Factor-alpha; D019010:Vascular Cell Adhesion Molecule-1; C038649:13-hydroperoxy-9,11-octadecadienoic acid