ENHANCED LEVELS OF LIPOPEROXIDES IN LOW-DENSITY-LIPOPROTEIN INCUBATEDWITH MURINE FIBROBLASTS EXPRESSING HIGH-LEVELS OF HUMAN 15-LIPOXYGENASE

There is strong experimental evidence that oxidized low density lipopr otein (Ox-LDL) plays an important role in atherosclerosis. However, th e mechanisms by which Ox-LDL is formed in vivo are unknown. To test wh ether 15 lipoxygenase (15-LO) could play a role in oxidation of LDL by cells, we expressed 15-LO activity in murine fibroblasts, which do no t normally have 15-LO activity, and tested their ability to modify LDL . Using a retroviral vector, we prepared fibroblasts that expressed 2- to more 15-LO activity than 20-fold control fibroblasts infected with a vector containing beta-galactosidase (lacZ). Compared with LDL incu bated with lacZ cells, LDL incubated with 15-LO-containing cells were enriched with lipid hydroperoxides. When these LDL samples were subseq uently subjected to oxidative stress, they were more susceptible to fu rther oxidative modification, as judged by increased conjugated diene formation and by increased ability to compete with I-125-Ox-LDL for up take by macrophages. These findings establish that cellular 15-LO can contribute to oxidative modification of LDL, but the quantitative sign ificance of these findings to the in vivo oxidation of LDL remains to be established.