Acidity increases the uptake of native LDL by human monocyte-derived macrophages

The extracellular pH is locally decreased in advanced atherosclerotic lesions, particularly in lipid-rich areas of the lesions. Since accumulation of LDL-derived cholesterol and formation of foam cells are key processes in atherogenesis, we tested here the effects of acidic pH on the uptake of native LDL. First, human monocytes were differentiated into macrophages in the presence of granulocyte–monocyte-colony stimulating factor (GM-CSF) after which native LDL was applied to the monocyte-derived macrophages at pH 5.5, 6.5, or 7.5 and the binding and uptake of LDL by macrophages were determined. The lower the pH was, the higher was the binding and uptake of LDL by macrophages. Also, acidic pH was found to increase the production of cell surface proteoglycans by macrophages and binding of LDL to the glycosaminoglycan chains of the proteoglycans. The acidity-induced increase in the uptake of LDL by macrophages could be inhibited by pretreating the cells with heparinase and chondroitinase as well as by inhibiting the production of proteoglycans with NaClO3. Thus, the observed increase in the uptake of native LDL to macrophages appears to depend on the increased ability of LDL to bind to cell surface proteoglycans at acidic pH. Taken together, our present results indicate that acidity increases the effective concentration of LDL on macrophage surfaces by increasing the amount of cell surface proteoglycans and by enhancing the binding of LDL to them and so promotes LDL uptake with ensuing foam cell formation.