Inducible Expression of Lectin-like Oxidized Low Density Lipoprotein Receptor-1 in Vascular Endothelial Cells and Macrophages

Abstract

Endothelial dysfunction, or activation, elicited by oxidized low density lipoprotein (Ox-LDL) or its lipid constituent, has been implicated in the initiation and progression of atherosclerosis. We have recently identified a C-type lectin-like molecule, designated lectin-like Ox-LDL receptor-1 (LOX-1), which acts as a cell-surface receptor for Ox-LDL in cultured vascular endothelial cells. In this report, we provide evidence that LOX-1 expression can be upregulated by tumor necrosis factor -α (TNF-α) and phorbol myristate acetate (PMA) in cultured bovine aortic endothelial cells. TNF-α and PMA upregulated LOX-1 protein and mRNA expression in a time- and dose-dependent manner. Nuclear run-off assay revealed TNF-α and fluid shear stress stimulates transcription of LOX-1 gene. CHO-K1 cells stably expressing LOX-1 internalized Dil-labeled Ox-LDL but not significantly acetylated LDL (Ac-LDL), which was effectively suppressed by excess amounts of unlabeled Ox-LDL but not by Ac-LDL. Upregulated expression of LOX-1 by TNF-a and PMA was associated with increased uptake of Dil-Ox-LDL that can not be blocked by excess amounts of unlabeled Ac-LDL. LOX-1 expression was also detectable in human peripheral blood monocytes after macrophage-like differentiation in vitro, the moncytic cell line THP-1 cells after macrophage-like differentiation by PMA, and murine peritoneal macrophages. Taken together, LOX-1 is a receptor specific for Ox-LDL, and enhanced uptake of Ox-LDL via this novel receptor on vascular endothelial cells and macrophages may play important roles in both endothelial activation and foam cell transformation of macrophages in atherogenesis.