TRANSGENIC RABBITS WITH THE INTEGRATED HUMAN 15-LIPOXYGENASE GENE DRIVEN BY A LYSOZYME PROMOTER - MACROPHAGE-SPECIFIC EXPRESSION AND VARIABLE POSITIONAL SPECIFICITY OF THE TRANSGENIC ENZYME

15-lipoxygenase is expressed in foamy macrophages of atherosclerotic l esions and has been implicated in the oxidative modification of low de nsity lipoprotein during early stages of atherogenesis. To establish a n animal model of 15-lipoxygenase overexpression, we created transgeni c rabbits that express at high level the human 15-lipoxygenase in mono cyte-derived macrophages but not in liver, heart, kidney, lung, or oth er tissues. The expression level of the enzyme in monocyte-derived mac rophages is comparable to that of interleukin 4 (IL4)-treated human mo nocytes, but more than 20-fold higher than in macrophages of normal ra bbits. The transgenic enzyme oxygenates linoleic acid to 13S-hydropero xy-9, 11 (Z,E)-octadecadienoic acid (13-HODE), and arachidonic acid to a mixture of 12S-hydroperoxy-5, 8, 10, 14 (Z,Z,E,Z)-eicosatetraenoic acid (12S-HETE), and 15S-hydroperoxy-5, 8, 11, 14 (Z,Z,Z,E)-eicosatetr aenoic acid (15S-HETE). The 12-HETE/15-HETE ratio varied between 0.3 a nd 5.4, indicating a remarkable variability in the positional specific ity of the transgenic enzyme. Macrophages from normal rabbits consiste ntly produced 12S-HETE as the major oxygenation product. 15-lipoxygena se-overexpressing rabbits may be used for further mechanistic studies on the implication of lipoxygenase in atherogenesis; they are also an ideal model for testing the in vivo action of 15-lipoxygenase inhibito rs.