Trans‐plasma membrane electron transport induces macrophage‐mediated low‐density lipoprotein oxidation

Oxidation of low‐density lipoprotein (LDL) in the arterial intima has been implicated in atherogenesis. The exact mechanism of this oxidation, however, remains unclear. In the present study we investigated the role of the trans‐plasma membrane electron transport (TPMET) system of macrophages in cell‐mediated LDL oxidation. We demonstrated that TPMET of mouse and human macrophages, measured as reduction of the impermeable oxidant ferricyanide (FEC), was enhanced strongly by loading macrophages with ascorbate (Asc). This appoach also enhanced the ability of cells to oxidize LDL in Ham's F‐10 medium. The stimulatory effect of Ascenrichment of macrophages on both processes was not due to release of Asc or other reductants into the medium, as demonstrated by the lack of the effects of ascorbate oxidase and the inhibitors of cellular Asc‐recycling on these processes. This conclusion is also supported by experiments in which we analyzed the amounts of Asc and DHA secreted by cells and tested their effect of LDL oxidation, and also measured the ability of cell‐conditioned medium from control and Asc‐enriched cells to reduce FEC. We conclude that TPMET is largely responsible for macrophage‐mediated LDL oxidation by means of its capacity to reduce extracellular transition metals.