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 lesions and has been implicated in the oxidative modification of low density lipoprotein during early stages of athero- genesis. To establish an animal model of 15-lipoxygenase overexpression, we created transgenic rabbits that express at high level the human 15-lipoxygenase in monocyte-derived macrophages but not in liver, heart, kidney, lung, or other tissues. The expression level of the enzyme in monocyte-derived macrophages is comparable to that of interleukin 4 (IL4) -treated human monocytes, but more than 20-fold higher than in macrophages of normal rabbits. The transgenic enzyme oxygenates linoleic acid to 13S- hydroperoxy-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)-ei- cosatetraenoic acid (12S-HETE), and 15S-hydrop- eroxy-5, 8, 11, 14 (Z, Z, Z, E)-eicosatetraenoic acid (15S-HETE). The 12-HETE/15-HETE ratio varied between 0.3 and 5.4, indicating a remarkable variability in the positional specificity of the transgenic enzyme. Macrophages from normal rabbits consistently produced 12S-HETE as the major oxygenation product. 15-Lipoxygenase-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 inhibitors.—Shen, J., KÜhn, H., Petho-Schramm, A., Chan, L. 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. FASEB J. 9, 1623-1631 (1995)