Primate Monocytes - CD14, CD16 - Ziegler-Heitbrock

Induced expression of manganese superoxide dismutase by non toxic concentrations of oxidized low density lipoprotein (oxLDL) protects against oxLDL-mediated cytotoxicity

Abstract

Oxidized low density lipoproteins (oxLDL) affect macrophages and play a critical role in the development of atherosclerosis. Here we demonstrate that high concentrations of oxLDL provoked apoptosis of human Mono-Mac-6 cells, which was blocked by diphenyleniodonium (DPI), an inhibitor of flavin-containing enzymes, such as NADPH oxidase, suggesting the involvement of reactive oxygen species (ROS). Importantly, pretreatment of cells with low concentrations of oxLDL prevented apoptosis in response to high concentrations of oxLDL by up-regulating manganese superoxide dismutase (MnSOD). DPI prevented expression of MnSOD by oxLDL, whereas inhibitors of cytochrome P450 (methoxalen) or xanthine oxidase (allopurinol) did not, thus pointing to a role of NADPH oxidase-derived ROS in oxLDL-induced MnSOD expression. Transfection of cells with MnSOD antisense but not scrambled antisense oligonucleotides significantly attenuated oxLDL-mediated MnSOD expression and hindered cytoprotective effects of non-toxic oxLDL concentrations. Our findings suggest that up-regulation of MnSOD by low concentrations of oxLDL is critical for protection towards oxLDL-mediated cytotoxicity.