Journal of Lipid Research (Apr 2005)
High-level lipoprotein [a] expression in transgenic mice: evidence for oxidized phospholipids in lipoprotein [a] but not in low density lipoproteins
- Matthias Schneider,
- Joseph L. Witztum,
- Stephen G. Young,
- Erwin H. Ludwig,
- Elizabeth R. Miller,
- Sotirios Tsimikas,
- Linda K. Curtiss,
- Santica M. Marcovina,
- John M. Taylor,
- Richard M. Lawn,
- Thomas L. Innerarity,
- Robert E. Pitas
Affiliations
- Matthias Schneider
- Gladstone Institute of Cardiovascular Disease, University of California, San Francisco, CA 94158; Cardiovascular Research Institute, University of California, San Francisco, CA 94158; Department of Medicine, University of California, San Diego, La Jolla, CA 92093; Department of Medicine, University of California, San Francisco, CA 94158; Department of Immunology, Scripps Research Institute, La Jolla, CA 92037; Department of Medicine, Northwest Lipid Research Laboratories, University of Washington, Seattle, WA 98103; Department of Physiology, University of California, San Francisco, CA 94158; CV Therapeutics, Palo Alto, CA 94304; Department of Pathology, University of California, San Francisco, CA 94158; Gladstone Institute of Neurological Disease, University of California, San Francisco, CA 94158
- Joseph L. Witztum
- Gladstone Institute of Cardiovascular Disease, University of California, San Francisco, CA 94158; Cardiovascular Research Institute, University of California, San Francisco, CA 94158; Department of Medicine, University of California, San Diego, La Jolla, CA 92093; Department of Medicine, University of California, San Francisco, CA 94158; Department of Immunology, Scripps Research Institute, La Jolla, CA 92037; Department of Medicine, Northwest Lipid Research Laboratories, University of Washington, Seattle, WA 98103; Department of Physiology, University of California, San Francisco, CA 94158; CV Therapeutics, Palo Alto, CA 94304; Department of Pathology, University of California, San Francisco, CA 94158; Gladstone Institute of Neurological Disease, University of California, San Francisco, CA 94158
- Stephen G. Young
- Gladstone Institute of Cardiovascular Disease, University of California, San Francisco, CA 94158; Cardiovascular Research Institute, University of California, San Francisco, CA 94158; Department of Medicine, University of California, San Diego, La Jolla, CA 92093; Department of Medicine, University of California, San Francisco, CA 94158; Department of Immunology, Scripps Research Institute, La Jolla, CA 92037; Department of Medicine, Northwest Lipid Research Laboratories, University of Washington, Seattle, WA 98103; Department of Physiology, University of California, San Francisco, CA 94158; CV Therapeutics, Palo Alto, CA 94304; Department of Pathology, University of California, San Francisco, CA 94158; Gladstone Institute of Neurological Disease, University of California, San Francisco, CA 94158
- Erwin H. Ludwig
- Gladstone Institute of Cardiovascular Disease, University of California, San Francisco, CA 94158; Cardiovascular Research Institute, University of California, San Francisco, CA 94158; Department of Medicine, University of California, San Diego, La Jolla, CA 92093; Department of Medicine, University of California, San Francisco, CA 94158; Department of Immunology, Scripps Research Institute, La Jolla, CA 92037; Department of Medicine, Northwest Lipid Research Laboratories, University of Washington, Seattle, WA 98103; Department of Physiology, University of California, San Francisco, CA 94158; CV Therapeutics, Palo Alto, CA 94304; Department of Pathology, University of California, San Francisco, CA 94158; Gladstone Institute of Neurological Disease, University of California, San Francisco, CA 94158
- Elizabeth R. Miller
- Gladstone Institute of Cardiovascular Disease, University of California, San Francisco, CA 94158; Cardiovascular Research Institute, University of California, San Francisco, CA 94158; Department of Medicine, University of California, San Diego, La Jolla, CA 92093; Department of Medicine, University of California, San Francisco, CA 94158; Department of Immunology, Scripps Research Institute, La Jolla, CA 92037; Department of Medicine, Northwest Lipid Research Laboratories, University of Washington, Seattle, WA 98103; Department of Physiology, University of California, San Francisco, CA 94158; CV Therapeutics, Palo Alto, CA 94304; Department of Pathology, University of California, San Francisco, CA 94158; Gladstone Institute of Neurological Disease, University of California, San Francisco, CA 94158
- Sotirios Tsimikas
- Gladstone Institute of Cardiovascular Disease, University of California, San Francisco, CA 94158; Cardiovascular Research Institute, University of California, San Francisco, CA 94158; Department of Medicine, University of California, San Diego, La Jolla, CA 92093; Department of Medicine, University of California, San Francisco, CA 94158; Department of Immunology, Scripps Research Institute, La Jolla, CA 92037; Department of Medicine, Northwest Lipid Research Laboratories, University of Washington, Seattle, WA 98103; Department of Physiology, University of California, San Francisco, CA 94158; CV Therapeutics, Palo Alto, CA 94304; Department of Pathology, University of California, San Francisco, CA 94158; Gladstone Institute of Neurological Disease, University of California, San Francisco, CA 94158
- Linda K. Curtiss
- Gladstone Institute of Cardiovascular Disease, University of California, San Francisco, CA 94158; Cardiovascular Research Institute, University of California, San Francisco, CA 94158; Department of Medicine, University of California, San Diego, La Jolla, CA 92093; Department of Medicine, University of California, San Francisco, CA 94158; Department of Immunology, Scripps Research Institute, La Jolla, CA 92037; Department of Medicine, Northwest Lipid Research Laboratories, University of Washington, Seattle, WA 98103; Department of Physiology, University of California, San Francisco, CA 94158; CV Therapeutics, Palo Alto, CA 94304; Department of Pathology, University of California, San Francisco, CA 94158; Gladstone Institute of Neurological Disease, University of California, San Francisco, CA 94158
- Santica M. Marcovina
- Gladstone Institute of Cardiovascular Disease, University of California, San Francisco, CA 94158; Cardiovascular Research Institute, University of California, San Francisco, CA 94158; Department of Medicine, University of California, San Diego, La Jolla, CA 92093; Department of Medicine, University of California, San Francisco, CA 94158; Department of Immunology, Scripps Research Institute, La Jolla, CA 92037; Department of Medicine, Northwest Lipid Research Laboratories, University of Washington, Seattle, WA 98103; Department of Physiology, University of California, San Francisco, CA 94158; CV Therapeutics, Palo Alto, CA 94304; Department of Pathology, University of California, San Francisco, CA 94158; Gladstone Institute of Neurological Disease, University of California, San Francisco, CA 94158
- John M. Taylor
- Gladstone Institute of Cardiovascular Disease, University of California, San Francisco, CA 94158; Cardiovascular Research Institute, University of California, San Francisco, CA 94158; Department of Medicine, University of California, San Diego, La Jolla, CA 92093; Department of Medicine, University of California, San Francisco, CA 94158; Department of Immunology, Scripps Research Institute, La Jolla, CA 92037; Department of Medicine, Northwest Lipid Research Laboratories, University of Washington, Seattle, WA 98103; Department of Physiology, University of California, San Francisco, CA 94158; CV Therapeutics, Palo Alto, CA 94304; Department of Pathology, University of California, San Francisco, CA 94158; Gladstone Institute of Neurological Disease, University of California, San Francisco, CA 94158
- Richard M. Lawn
- Gladstone Institute of Cardiovascular Disease, University of California, San Francisco, CA 94158; Cardiovascular Research Institute, University of California, San Francisco, CA 94158; Department of Medicine, University of California, San Diego, La Jolla, CA 92093; Department of Medicine, University of California, San Francisco, CA 94158; Department of Immunology, Scripps Research Institute, La Jolla, CA 92037; Department of Medicine, Northwest Lipid Research Laboratories, University of Washington, Seattle, WA 98103; Department of Physiology, University of California, San Francisco, CA 94158; CV Therapeutics, Palo Alto, CA 94304; Department of Pathology, University of California, San Francisco, CA 94158; Gladstone Institute of Neurological Disease, University of California, San Francisco, CA 94158
- Thomas L. Innerarity
- Gladstone Institute of Cardiovascular Disease, University of California, San Francisco, CA 94158; Cardiovascular Research Institute, University of California, San Francisco, CA 94158; Department of Medicine, University of California, San Diego, La Jolla, CA 92093; Department of Medicine, University of California, San Francisco, CA 94158; Department of Immunology, Scripps Research Institute, La Jolla, CA 92037; Department of Medicine, Northwest Lipid Research Laboratories, University of Washington, Seattle, WA 98103; Department of Physiology, University of California, San Francisco, CA 94158; CV Therapeutics, Palo Alto, CA 94304; Department of Pathology, University of California, San Francisco, CA 94158; Gladstone Institute of Neurological Disease, University of California, San Francisco, CA 94158
- Robert E. Pitas
- Gladstone Institute of Cardiovascular Disease, University of California, San Francisco, CA 94158; Cardiovascular Research Institute, University of California, San Francisco, CA 94158; Department of Medicine, University of California, San Diego, La Jolla, CA 92093; Department of Medicine, University of California, San Francisco, CA 94158; Department of Immunology, Scripps Research Institute, La Jolla, CA 92037; Department of Medicine, Northwest Lipid Research Laboratories, University of Washington, Seattle, WA 98103; Department of Physiology, University of California, San Francisco, CA 94158; CV Therapeutics, Palo Alto, CA 94304; Department of Pathology, University of California, San Francisco, CA 94158; Gladstone Institute of Neurological Disease, University of California, San Francisco, CA 94158
- Journal volume & issue
-
Vol. 46,
no. 4
pp. 769 – 778
Abstract
Efforts to elucidate the role of lipoprotein [a] (Lp[a]) in atherogenesis have been hampered by the lack of an animal model with high plasma Lp[a] levels. We produced two lines of transgenic mice expressing apolipoprotein [a] (apo[a]) in the liver and crossed them with mice expressing human apolipoprotein B-100 (apoB-100), generating two lines of Lp[a] mice. One had Lp[a] levels of ∼700 mg/dl, well above the 30 mg/dl threshold associated with increased risk of atherosclerosis in humans; the other had levels of ∼35 mg/dl. Most of the LDL in mice with high-level apo[a] expression was covalently bound to apo[a], but most of the LDL in the low-expressing line was free. Using an enzyme-linked sandwich assay with monoclonal antibody EO6, we found high levels of oxidized phospholipids in Lp[a] from high-expressing mice but not in LDL from low-expressing mice or in LDL from human apoB-100 transgenic mice (P < 0.00001), even though all mice had similar plasma levels of human apoB-100.The increase in oxidized lipids specific to Lp[a] in high-level apo[a]-expressing mice suggests a mechanism by which increased circulating levels of Lp[a] could contribute to atherogenesis.
