Published online before print March 4, 2004, doi: 10.1161/01.RES.0000124920.09738.26
© 2004 American Heart Association, Inc.
Molecular Medicine |
Glucose Enhances Human Macrophage LOX-1 Expression
Role for LOX-1 in Glucose-Induced Macrophage Foam Cell Formation
From the Department of Biomedical Sciences (L.L.) and Medicine (G.R.), University of Montreal, Centre Hospitalier de l’Université de Montréal (CHUM) Research Centre, Notre-Dame Hospital, Montreal, Quebec, Canada, and the Department of Bioscience (T.S.), National Cardiovascular Center Research Institute, Fujishirodai, Suita, Osaka, Japan.
Correspondence to Dr Geneviève Renier, CHUM Research Centre, Notre-Dame Hospital, J.-A. De Seve Pavilion, Door Y 3622, 1560 Sherbrooke St E, Montreal, Quebec H2L 4M1, Canada. E-mail genevieve.renier{at}umontreal.ca
Lectin-like oxidized LDL receptor-1 (LOX-1) is a newly identified receptor for oxidized LDL that is expressed by vascular cells. LOX-1 is upregulated in aortas of diabetic rats and thus may contribute to the pathogenesis of human diabetic atherosclerosis. In this study, we examined the regulation of human monocyte-derived macrophage (MDM) LOX-1 expression by high glucose and the role of LOX-1 in glucose-induced foam cell formation. Incubation of human MDMs with glucose (5.6 to 30 mmol/L) enhanced, in a dose- and time-dependent manner, LOX-1 gene and protein expression. Induction of LOX-1 gene expression by high glucose was abolished by antioxidants, protein kinase C (PKC), mitogen-activated protein kinases (MAPKs), nuclear factor-
B (NF-B), and activated protein-1 (AP-1) inhibitors. In human MDMs cultured with high glucose, increased expression of PKCß2 and enhanced phosphorylation of extracellular signal-regulated protein kinase 1/2 was observed. Activation of these kinases was inhibited by the antioxidant N-acetyl-L-cysteine (NAC) and by the PKCß inhibitor LY379196. High glucose also enhanced the binding of nuclear proteins extracted from human MDMs to the NF-B and AP-1 regulatory elements of the LOX-1 gene promoter. This effect was abrogated by NAC and PKC/MAPK inhibitors. Finally, high glucose induced human macrophage-derived foam cell formation through a LOX-1–dependent pathway. Overall, these results demonstrate that high glucose concentrations enhance LOX-1 expression in human MDMs and that this effect is associated with foam cell formation. Pilot data showing that MDMs of patients with type 2 diabetes overexpress LOX-1 support the relevance of this work to human diabetic atherosclerosis.
Key Words: macrophages • lectin-like oxidized low-density lipoprotein receptor-1 • glucose • diabetes • foam cell formation
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