Expression of 12/15-Lipoxygenase Attenuates Intracellular Lipid Deposition During In Vitro Foam Cell Formation

Abstract

Lipoxygenases with different positional specificity have been implicated in atherogenesis, but the precise roles of the various isoforms remain unclear. Because of its capability of oxidizing low-density lipoprotein (LDL) to an atherogenic form, 12/15-lipoxygenases have been suggested to initiate LDL oxidation in vivo; thus, these enzymes may exhibit pro-atherogenic activities. However, in several rabbit atherosclerosis models, the enzyme appears to act atheroprotective. To test the impact of 12/15-lipoxygenase expression on early atherogenesis, we established an in vitro foam cell model, which is based on the uptake of acetylated LDL by murine macrophages. In this system, we found that 12/15-lipoxygenase expression protects the cells from intracellular lipid deposition. This effect was related to an attenuated uptake of modified LDL, as indicated by impaired expression of scavenger receptor A and to accelerated intracellular lipid metabolism. Our results indicate that the role of 12/15-lipoxygenase in atherogenesis may not be restricted to oxidative LDL modification. Expression of this lipid-peroxidizing enzyme may impact both lipid uptake and intracellular lipid turnover. These data provide a plausible explanation for the antiatherogenic effect of 12/15-LOX in rabbit atherosclerosis models.