Overexpression of 15-lipoxygenase in vascular endothelium accelerates early atherosclerosis in LDL receptor-deficient mice

To study the possible role of the human lipid-oxidizing enzyme 15-lipoxygen ase (15-LO) in atherosclerosis, we overexpressed it specifically in the vas cular wall of C57B6/SJL mice by using the murine preproendothelin-1 promote r. The-mice overexpressing 15-LO were crossbred with low density lipoprotei n (LDL) receptor-deficient mice to investigate atherogenesis. High levels o f 15-LO were expressed in the atherosclerotic lesion in the double-transgen ic mice as assessed by immunohistochemistry. The double-transgenic, 15-LO- overexpressing, LDL receptor-deficient mice (LDLR-/-/15LO) developed signif icantly larger atherosclerotic lesions at the aortic sinus compared with le sions in the LDL receptor-deficient (LDLR-/-) mice after 3 and 6 weeks (107 000 versus 28 000 mu m(2) [P<0.001] and 121 000 versus 87 000 mu m(2) P<0. 05], respectively) of an atherogenic diet. LDL from the LDLR-/-/15LO mice w as 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 se rum 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, thes e results support the hypothesis that 15-LO overexpression in the vessel wa ll is associated with enhanced atherogenesis.