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-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 microm(2) [P:<0.001] and 121,000 versus 87,000 microm(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.
Harats
D
D
Institute of Lipid & Atherosclerosis Research, Sheba Medical Center, Tel-Hashomer, Israel. dharats@post.tau.ac.il
Shaish
A
A
George
J
J
Mulkins
M
M
Kurihara
H
H
Levkovitz
H
H
Sigal
E
E
D000818:Animals; D000906:Antibodies / Q000097:blood; D001093:Arachidonate 15-Lipoxygenase / Q000096:biosynthesis / Q000502:physiology*; D001161:Arteriosclerosis / Q000201:enzymology*; D019332:Endothelin-1; D016232:Endothelins / Q000235:genetics; D004730:Endothelium, Vascular / Q000201:enzymology*; D008055:Lipids / Q000097:blood; D008074:Lipoproteins / Q000378:metabolism; D008077:Lipoproteins, LDL / Q000276:immunology; D051379:Mice; D008822:Mice, Transgenic; D010084:Oxidation-Reduction; D011498:Protein Precursors / Q000235:genetics; D011973:Receptors, LDL / Q000172:deficiency / Q000378:metabolism*
D000906:Antibodies; D019332:Endothelin-1; D016232:Endothelins; D008055:Lipids; D008074:Lipoproteins; D008077:Lipoproteins, LDL; D011498:Protein Precursors; D011973:Receptors, LDL; C099252:oxidized low density lipoprotein; D001093:Arachidonate 15-Lipoxygenase