© 2000 American Heart Association, Inc.
Atherosclerosis and Lipoproteins |
Overexpression of 15-Lipoxygenase in Vascular Endothelium Accelerates Early Atherosclerosis in LDL Receptor–Deficient Mice
From the Institute of Lipid & Atherosclerosis Research (D.H., A.S., J.G., H.L.), Sheba Medical Center, Tel-Hashomer, Israel; Bristol-Myers Squibb (M.M., E.S.), Princeton, NJ; and the Third Department of Medicine (H.K.), University of Tokyo, Hongo, Tokyo, Japan.
Correspondence to Dror Harats, MD, Institute of Lipid & Atherosclerosis Research, Sheba Medical Center, Tel-Hashomer, 52621 Israel. E-mail dharats{at}post.tau.ac.il
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 µm2 [P<0.001] and 121 000 versus 87 000 µm2 [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.
Key Words: 15-lipoxygenase • oxidation • endothelium • gene expression • atherosclerosis
This article has been cited by other articles:
 |
|
 |
|
  S. Agrawal, M. Febbraio, E. Podrez, M. K. Cathcart, G. R. Stark, and G. M. Chisolm Signal Transducer and Activator of Transcription 1 Is Required for Optimal Foam Cell Formation and Atherosclerotic Lesion Development Circulation, June 12, 2007; 115(23): 2939 - 2947. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. E. Kanter, F. Johansson, R. C. LeBoeuf, and K. E. Bornfeldt Do Glucose and Lipids Exert Independent Effects on Atherosclerotic Lesion Initiation or Progression to Advanced Plaques? Circ. Res., March 30, 2007; 100(6): 769 - 781. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. A. Bostrom, B. B. Boyanovsky, C. T. Jordan, M. P. Wadsworth, D. J. Taatjes, F. C. de Beer, and N. R. Webb Group V Secretory Phospholipase A2 Promotes Atherosclerosis: Evidence From Genetically Altered Mice Arterioscler. Thromb. Vasc. Biol., March 1, 2007; 27(3): 600 - 606. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Hamerman Osteoporosis and atherosclerosis: biological linkages and the emergence of dual-purpose therapies QJM, July 1, 2005; 98(7): 467 - 484. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S.-L. Li, R. S. Dwarakanath, Q. Cai, L. Lanting, and R. Natarajan Effects of silencing leukocyte-type 12/15-lipoxygenase using short interfering RNAs J. Lipid Res., February 1, 2005; 46(2): 220 - 229. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. K. Rydberg, A. Krettek, C. Ullstrom, K. Ekstrom, P.-A. Svensson, L. M.S. Carlsson, A.-C. Jonsson-Rylander, G. I. Hansson, W. McPheat, O. Wiklund, et al. Hypoxia Increases LDL Oxidation and Expression of 15-Lipoxygenase-2 in Human Macrophages Arterioscler. Thromb. Vasc. Biol., November 1, 2004; 24(11): 2040 - 2045. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. J. Barter, S. Nicholls, K.-A. Rye, G.M. Anantharamaiah, M. Navab, and A. M. Fogelman Antiinflammatory Properties of HDL Circ. Res., October 15, 2004; 95(8): 764 - 772. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Huo, L. Zhao, M. C. Hyman, P. Shashkin, B. L. Harry, T. Burcin, S. B. Forlow, M. A. Stark, D. F. Smith, S. Clarke, et al. Critical Role of Macrophage 12/15-Lipoxygenase for Atherosclerosis in Apolipoprotein E-Deficient Mice Circulation, October 5, 2004; 110(14): 2024 - 2031. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Natarajan and J. L. Nadler Lipid Inflammatory Mediators in Diabetic Vascular Disease Arterioscler. Thromb. Vasc. Biol., September 1, 2004; 24(9): 1542 - 1548. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Navab, G. M. Ananthramaiah, S. T. Reddy, B. J. Van Lenten, B. J. Ansell, G. C. Fonarow, K. Vahabzadeh, S. Hama, G. Hough, N. Kamranpour, et al. Thematic review series: The Pathogenesis of Atherosclerosis The oxidation hypothesis of atherogenesis: the role of oxidized phospholipids and HDL J. Lipid Res., June 1, 2004; 45(6): 993 - 1007. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. B. Reilly, S. Srinivasan, M. E. Hatley, M. K. Patricia, J. Lannigan, D. T. Bolick, G. Vandenhoff, H. Pei, R. Natarajan, J. L. Nadler, et al. 12/15-Lipoxygenase Activity Mediates Inflammatory Monocyte/Endothelial Interactions and Atherosclerosis in Vivo J. Biol. Chem., March 5, 2004; 279(10): 9440 - 9450. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. F. Klein, J. Allard, Z. Avnur, T. Nikolcheva, D. Rotstein, A. S. Carlos, M. Shea, R. V. Waters, J. K. Belknap, G. Peltz, et al. Regulation of Bone Mass in Mice by the Lipoxygenase Gene Alox15 Science, January 9, 2004; 303(5655): 229 - 232. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. A. VanderLaan, C. A. Reardon, and G. S. Getz Site Specificity of Atherosclerosis: Site-Selective Responses to Atherosclerotic Modulators Arterioscler. Thromb. Vasc. Biol., January 1, 2004; 24(1): 12 - 22. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
X. Tang, N. Spitzbarth, H. Kuhn, P. Chaitidis, and W. B. Campbell Interleukin-13 Upregulates Vasodilatory 15-Lipoxygenase Eicosanoids in Rabbit Aorta Arterioscler. Thromb. Vasc. Biol., October 1, 2003; 23(10): 1768 - 1774. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. E. Hatley, S. Srinivasan, K. B. Reilly, D. T. Bolick, and C. C. Hedrick Increased Production of 12/15 Lipoxygenase Eicosanoids Accelerates Monocyte/Endothelial Interactions in Diabetic db/db Mice J. Biol. Chem., July 3, 2003; 278(28): 25369 - 25375. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Kuhn, M. Anton, C. Gerth, and A. Habenicht Amino Acid Differences in the Deduced 5-Lipoxygenase Sequence of CAST Atherosclerosis-Resistance Mice Confer Impaired Activity When Introduced Into the Human Ortholog Arterioscler. Thromb. Vasc. Biol., June 1, 2003; 23(6): 1072 - 1076. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Zhu, Y. Takahashi, W. Xu, H. Kawajiri, T. Murakami, M. Yamamoto, S. Iseki, T. Iwasaki, H. Hattori, and T. Yoshimoto Low Density Lipoprotein Receptor-related Protein-mediated Membrane Translocation of 12/15-Lipoxygenase Is Required for Oxidation of Low Density Lipoprotein by Macrophages J. Biol. Chem., April 4, 2003; 278(15): 13350 - 13355. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Spanbroek, R. Grabner, K. Lotzer, M. Hildner, A. Urbach, K. Ruhling, M. P. W. Moos, B. Kaiser, T. U. Cohnert, T. Wahlers, et al. Expanding expression of the 5-lipoxygenase pathway within the arterial wall during human atherogenesis PNAS, February 4, 2003; 100(3): 1238 - 1243. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Fuentes, M. Hernandez, F. J. Fernandez-Aviles, M. S. Crespo, and M. L. Nieto Cooperation Between Secretory Phospholipase A2 and TNF-Receptor Superfamily Signaling: Implications for the Inflammatory Response in Atherogenesis Circ. Res., October 18, 2002; 91(8): 681 - 688. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Zhao, C. A. Cuff, E. Moss, U. Wille, T. Cyrus, E. A. Klein, D. Pratico, D. J. Rader, C. A. Hunter, E. Pure, et al. Selective Interleukin-12 Synthesis Defect in 12/15-Lipoxygenase-deficient Macrophages Associated with Reduced Atherosclerosis in a Mouse Model of Familial Hypercholesterolemia J. Biol. Chem., September 13, 2002; 277(38): 35350 - 35356. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. E. Rosenfeld Leukocyte Recruitment Into Developing Atherosclerotic Lesions: The Complex Interaction Between Multiple Molecules Keeps Getting More Complex Arterioscler. Thromb. Vasc. Biol., March 1, 2002; 22(3): 361 - 363. [Full Text] [PDF]
|
|
|
|
|
|
J. George, A. Afek, A. Shaish, H. Levkovitz, N. Bloom, T. Cyrus, L. Zhao, C. D. Funk, E. Sigal, and D. Harats 12/15-Lipoxygenase Gene Disruption Attenuates Atherogenesis in LDL Receptor-Deficient Mice Circulation, October 2, 2001; 104(14): 1646 - 1650. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. MERTENS and P. HOLVOET Oxidized LDL and HDL: antagonists in atherothrombosis FASEB J, October 1, 2001; 15(12): 2073 - 2084. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Heydeck, J. M. Upston, H. Viita, S. Yla-Herttuala, and R. Stocker Oxidation of LDL by rabbit and human 15-lipoxygenase: prevalence of nonenzymatic reactions J. Lipid Res., July 1, 2001; 42(7): 1082 - 1088. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. Xu, Y. Takahashi, T. Sakashita, T. Iwasaki, H. Hattori, and T. Yoshimoto Low Density Lipoprotein Receptor-related Protein Is Required for Macrophage-mediated Oxidation of Low Density Lipoprotein by 12/15-Lipoxygenase J. Biol. Chem., September 21, 2001; 276(39): 36454 - 36459. [Abstract] [Full Text] [PDF]
|
|