Enhanced Expression of Lectin-Like Oxidized LDL Receptor-1 is Implicated in the Sodium Arsenite-Induced Increase in Foam Cells from Murine Macrophages

Arsenic is a naturally occurring toxic element that is present in the air, food, soil, and water of many countries, including the U.S. The U.S. Geological Survey reported that about 44 million people in the U.S. use private wells for water and estimated that over 2 million of those people drink from wells with high concentrations (>10 ug/L) of arsenic. Epidemiological studies have shown that chronic arsenic exposure is a significant risk factor for cardiovascular diseases, including atherosclerosis. However, the cellular and molecular mechanisms connecting arsenic exposure to atherosclerosis are not known. It has been established that Macrophage-derived, lipid-loaded, foam cells are a key component of atherosclerotic plaques and are essential for their formation. Furthermore scavenger receptors, such as lectin-like oxLDL receptor 1 (LOX-1), CD36, and scavenger receptor type A (SR-A), regulate the lipid uptake of macrophages and are likely key to the transformation of these cells to foam cells. Our previous study showed that in mouse aortic endothelial cells, arsenic exposure stimulated the uptake of oxidized low-density lipoprotein (oxLDL) by upregulating the expression of LOX-1. To see if LOX-1 might play a key role in foam cell formation, in this study, we used Oil-red-O assay to show that sodium arsenite (SA) exposure dose-dependently enhanced the uptake of oxLDL in murine RAW 264.7 macrophages with a commensurate increase in foam cell count. In addition, while we showed that SA treatment caused a significant increase in both LOX-1 mRNA and protein levels, only slight or no significant increases were observed in CD36 or SR-A mRNA expression. Our results indicate that in arsenic induced atherosclerosis, LOX-1 may play a critical and perhaps unique role among scavenger receptors in the production of foam cells. Further studies, including in vivo and in vitro, are warranted to verify and clarify the role of Lox-1 in a disease model and to identify other cells and components of the disease pathway.