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Glucose Enhances Endothelial LOX-1 Expression

Role for LOX-1 in Glucose-Induced Human Monocyte Adhesion to Endothelium

¹ Department of Biomedical Sciences, University of Montreal, Centre Hospitalier de l’Université de Montréal (CHUM) Research Centre, Notre-Dame Hospital, Montreal, Quebec, Canada
² Department of Bioscience, National Cardiovascular Center Research Institute, Fujishirodai, Suita, Osaka, Japan
³ Department of Nutrition, University of Montreal, Centre Hospitalier de l’Université de Montréal (CHUM) Research Centre, Notre-Dame Hospital, Montreal, Quebec, Canada

Endothelial dysfunction is an early and key determinant of diabetic vascular complications that is elicited at least in part by oxidized LDL (oxLDL). The recent observation that lectin-like oxLDL receptor-1 (LOX-1) expression is increased in the vascular endothelium of diabetic rats suggests a role for LOX-1 in the pathogenesis of diabetic vascular dysfunction. Because postprandial plasma glucose has been recently proposed as an independent risk factor for cardiovascular diseases in patients with diabetes, we evaluated, in the current study, the in vitro effect of high glucose on LOX-1 expression by human aortic endothelial cells (HAECs) and the role of this receptor in glucose-induced human monocyte adhesion to endothelium. Exposure of HAECs to high D-glucose concentrations (5.6–30 mmol/l) enhanced, in a dose- and time-dependent manner, LOX-1 expression, both at the gene and protein levels. The stimulatory effect of glucose on LOX-1 gene expression in HAECs was abolished by antioxidants and inhibitors of nuclear factor (NF)-B, protein kinase C (PKC), and mitogen-activated protein kinases (MAPKs). Electrophoretic mobility shift assay data demonstrated that high glucose enhanced, in HAECs, the nuclear protein binding to the NF-B regulatory element of the LOX-1 gene. Finally, our results showed that incubation of HAECs with high glucose increased human monocyte adhesion to endothelium through a LOX-1—dependent signaling mechanism. Overall, these results demonstrate that high glucose induces endothelial LOX-1 expression. This effect appears to be exerted at the transcriptional level through increased oxidant stress and NF-B, PKC, and MAPK activation. The study also suggests a role for LOX-1 as mediator of the stimulatory effect of high glucose on monocyte adhesion.

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