Linoleic acid increases lectin-like oxidized LDL receptor-1 (LOX-1) expression in human aortic endothelial cells.
Results from in vitro studies suggest that selected fatty acids, and especially linoleic acid (LA), can elicit endothelial dysfunction (ED). Because LA is increased in all LDL subfractions in patients with type 2 diabetes, this alteration may contribute to ED associated with diabetes. Lectin-like oxidized LDL receptor-1 (LOX-1) is the major endothelial receptor for oxidized LDL (oxLDL), and uptake of oxLDL through LOX-1 induces ED. To evaluate whether LA may contribute to the upregulation of endothelial LOX-1 in diabetes, we studied the effect of LA on LOX-1 expression in cultured human aortic endothelial cells (HAECs). Treatment of HAECs with LA increased, in a time- and dose-dependent manner, endothelial LOX-1 protein expression. Pretreatment of HAECs with antioxidants and inhibitors of NADPH oxidase, protein kinase C (PKC), and nuclear factor-kappaB (NF-kappaB) inhibited the stimulatory effect of LA on LOX-1 protein expression. Furthermore, in LA-treated HAECs, increased expression of classic PKC isoforms was observed. LA also led to a significant increase in LOX-1 gene expression and enhanced the binding of nuclear proteins extracted from HAECs to the NF-kappaB regulatory element of the LOX-1 gene promoter. Finally, LA enhanced, through LOX-1, oxLDL uptake by endothelial cells. Overall, these results demonstrate that LA enhances endothelial LOX-1 expression through oxidative stress-sensitive and PKC-dependent pathways. This effect seems to be exerted at the transcriptional level and to involve the activation of NF-kappaB. Upregulation of LOX-1 by LA may contribute to ED associated with type 2 diabetes.
Maingrette
Fritz
F
Department of Nutrition, University of Montreal, Notre-Dame Hospital, CHUM Research Centre, 3rd Floor, Y-3622, 1560 Sherbrooke East, Montreal, Quebec, Canada, H2L 4M1.
Renier
Geneviève
G
D001011:Aorta; D001483:Base Sequence; D002478:Cells, Cultured; D017931:DNA Primers; D003924:Diabetes Mellitus, Type 2 / Q000503:physiopathology; D004730:Endothelium, Vascular / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D019787:Linoleic Acid / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics; D011973:Receptors, LDL / Q000235:genetics*; D051131:Receptors, Oxidized LDL; D051127:Scavenger Receptors, Class E; D014158:Transcription, Genetic / Q000187:drug effects
D017931:DNA Primers; C495137:OLR1 protein, human; D012333:RNA, Messenger; D011973:Receptors, LDL; D051131:Receptors, Oxidized LDL; D051127:Scavenger Receptors, Class E; D019787:Linoleic Acid