Overexpression of 15-Lipoxygenase in Vascular Endothelium Accelerates Early Atherosclerosis in LDL Receptor–Deficient Mice

Abstract

Abstract —To study the possible role of the human lipid-oxidizing enzyme 15-lipoxygenase (15-LO) in atherosclerosis, we overexpressed it specifically in the vascular wall of C57B6/SJL mice by using the murine preproendothelin-1 promoter. The mice overexpressing 15-LO were crossbred with low density lipoprotein (LDL) receptor–deficient mice to investigate atherogenesis. High levels of 15-LO were expressed in the atherosclerotic lesion in the double-transgenic mice as assessed by immunohistochemistry. The double-transgenic, 15-LO–overexpressing, LDL receptor–deficient mice (LDLR − /− /15LO) developed significantly larger atherosclerotic lesions at the aortic sinus compared with lesions in the LDL receptor–deficient (LDLR − /− ) mice after 3 and 6 weeks (107 000 versus 28 000 μm 2 [ P <0.001] and 121 000 versus 87 000 μm 2 [ P <0.05], respectively) of an atherogenic diet. LDL from the LDLR − /− /15LO mice was more susceptible to oxidation than was the LDL from the control LDLR − /− mice, as shown by a shorter lag period for copper-induced conjugated diene formation. On the other hand, no differences were found in the levels of serum anti–oxidized LDL antibodies between the study groups. There were also no differences with respect to the density of macrophages and T lymphocytes infiltrating the lesions in both experimental groups. Taken together, these results support the hypothesis that 15-LO overexpression in the vessel wall is associated with enhanced atherogenesis.