Elevation of plasma cholesterol is one of the major risk factors in the development of atherosclerosis. Oxidation of native LDL-cholesterol (nLDL), mainly by reactive oxygen species, leads to the formation of oxidized LDL (oxLDL). An important receptor for uptake of oxLDL is the lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1). LOX-1 is highly expressed on macrophages, but also present on endothelial and vascular smooth muscle cells. Especially the uptake by macrophages leads to the formation of foam cells, typically present in atherosclerotic lesions.
Aim of the present study was to analyze the impact of oxLDL on endothelial function and on LOX-1 expression in macrophages. In addition, we analyzed the effect of a western-type diet on endothelial function in mice that overexpress LOX-1 in endothelial cells.
To clarify the first question, we incubated aortic rings of wild-type mice with oxLDL and analyzed the endothelial function after 2 h of incubation using a Mulvany myograph. Compared to basal conditions, oxLDL significantly impaired endothelium-dependent vasodilation. To prove the concept of oxLDL and its receptor LOX-1 in endothelial cells, we fed mice that overexpress LOX-1 for 20 weeks a western-type diet and analyzed the endothelial function in the thoracic aorta. Interestingly, these mice showed no impairment of the endothelium-dependent relaxation after feeding a western-type diet. To get insights into LOX-1 regulation by oxLDL, we analyzed the impact of oxLDL on LOX-1 mRNA expression in human macrophages. Therefore monocytic THP-1 cells were phorbol myristate acetate differentiated into macrophages and stimulated for 24 h with nLDL and oxLDL. We found a significant induction of LOX-1 mRNA expression after oxLDL incubation, whereas nLDL showed no effect suggesting an increased oxLDL uptake in oxLDL-treated macrophages by increasing the LOX-1 receptor expression.
We underlined that oxLDL is a very important risk factor in the vascular wall by its ability of inducing endothelial dysfunction and LOX-1 in macrophages, two major processes in the development of atherosclerosis. Next experiments have to clarify the role of LOX-1 in endothelial cells.