Evidence for a dominant role of lipoxygenase(s) in the oxidation of LDL by mouse peritoneal macrophages.

It has been suggested that the oxidative modification of low density lipoprotein (LDL) is a key event in atherogenesis. Several mechanisms have been proposed to explain how different types of cells modify LDL. In this study we examine the relative contributions of superoxide anions and cellular lipoxygenase (LO) in the modification of LDL by macrophages. Superoxide dismutase (SOD) inhibited LDL oxidation by macrophages but only by 25%. Under the same conditions, several LO inhibitors (eicosatetraynoic acid (ETYA), piriprost, and A-64077) almost completely inhibited the modification of LDL by macrophages. SOD had a greater inhibitory effect on the modification of LDL by U937 cells and fibroblasts (32% and 64%, respectively) but again LO inhibitors had a much greater effect (79 to 100% inhibition). Incubation of [1-14C]linoleic acid with mouse peritoneal macrophages resulted in its conversion to a single more polar product coeluting with 13- and 9-HODE by reverse phase HPLC. When the cells were preincubated with LO inhibitors, formation of this product was significantly inhibited. It is concluded that the modification of LDL by macrophages is mediated in large part by lipoxygenase-type activity.