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Linoleic Acid Increases Lectin-Like Oxidized LDL Receptor-1 (LOX-1) Expression in Human Aortic Endothelial Cells

¹ Department of Nutrition, University of Montreal, Centre Hospitalier de l’Université de Montréal (CHUM) Research Centre, Notre-Dame Hospital, Montreal, Quebec, Canada
² Department of Medicine, University of Montreal, CHUM Research Centre, Notre-Dame Hospital, Montreal, Quebec, Canada

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-B (NF-B) 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-B 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-B. Upregulation of LOX-1 by LA may contribute to ED associated with type 2 diabetes.

Abbreviations: DiI-oxLDL, 1,1'-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine perchlorate-labeled oxLDL; ED, endothelial dysfunction; EGM, endothelial growth culture medium; HAEC, human aortic endothelial cell; LA, linoleic acid; LOX-1, lectin-like oxidized LDL receptor-1; NAC, N-acetyl-L-cysteine; oxLDL, oxidized LDL; NF, nuclear factor; PKC, protein kinase C; SR, scavenger receptor

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