Oxidized cholesteryl linoleates stimulate endothelial cells to bind monocytes via the extracellular signal-regulated kinase 1/2 pathway.
Oxidation products of cholesteryl esters have been shown to be present in oxidized low density lipoprotein and in atherosclerotic lesions. Monocyte adhesion to the endothelium is an initiating crucial event in atherogenesis. Here, we show that in vitro oxidized cholesteryl linoleate (oxCL) stimulated human umbilical vein endothelial cells (HUVECs) to bind human peripheral blood mononuclear cells as well as monocyte-like U937 cells but not peripheral blood neutrophils or neutrophil-like HL-60 cells. Among the oxidation products contained in oxCLs, 9-oxononanoyl cholesterol (9-ONC) and cholesteryl linoleate hydroperoxides stimulated U937 cell adhesion. OxCL-induced U937 cell adhesion was inhibited by an antibody against the connecting segment-1 region of fibronectin. Neither oxCL nor 9-ONC induced activation of the classical nuclear factor-kappaB pathway. In contrast, stimulation of HUVECs with oxCL resulted in phosphorylation of the extracellular signal-regulated kinase 1/2. Moreover, U937 cell adhesion induced by 9-ONC and oxCL was blocked by a mitogen-activated protein kinase/extracellular signal-regulated kinase inhibitor and a protein kinase C inhibitor. Taken together, oxCLs stimulate HUVECs to specifically bind monocytes, involving endothelial connecting segment-1 and the activation of a protein kinase C- and mitogen-activated protein kinase-dependent pathway. Thus, oxidized cholesteryl esters may play an important role as novel mediators in the initiation and progression of atherosclerosis.
Huber
Joakim
J
Department of Vascular Biology and Thrombosis Research, University of Vienna, Vienna, Austria.
Boechzelt
Herbert
H
Karten
Barbara
B
Surboeck
Michael
M
Bochkov
Valery N
VN
Binder
Bernd R
BR
Sattler
Wolfgang
W
Leitinger
Norbert
N
D001161:Arteriosclerosis / Q000209:etiology; D002448:Cell Adhesion / Q000187:drug effects* / Q000502:physiology; D002784:Cholesterol / Q000031:analogs & derivatives* / Q000494:pharmacology*; D002788:Cholesterol Esters / Q000494:pharmacology*; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D009000:Monocytes / Q000187:drug effects* / Q000502:physiology; D016328:NF-kappa B / Q000378:metabolism; D010084:Oxidation-Reduction; D010455:Peptides / Q000187:drug effects / Q000276:immunology; D010766:Phosphorylation; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D020298:U937 Cells / Q000187:drug effects
C114702:9-oxononanoyl cholesterol; D002788:Cholesterol Esters; D036341:Intercellular Signaling Peptides and Proteins; D016328:NF-kappa B; D010455:Peptides; C076687:CS1 peptide; C021976:cholesteryl linoleate; D002784:Cholesterol; D011493:Protein Kinase C; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases