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Journal of Lipid Research, Vol. 46, 769-778, April 2005
Copyright © 2005 by American Society for Biochemistry and Molecular Biology

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^*,, and Robert E. Pitas^1,*,,****

^* 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

¹ To whom correspondence should be addressed. e-mail: rpitas{at}gladstone.ucsf.edu

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.

Abbreviations: apo[a], apolipoprotein [a]; apoB-100, apolipoprotein B-100; FPLC, fast-performance liquid chromatography; IDL, intermediate density lipoprotein; Lp[a], lipoprotein [a]; MAb, monoclonal antibody; OxLDL, oxidized low density lipoprotein; RLU, relative light units

Supplementary key words atherosclerosis • oxidized low density lipoprotein • apolipoprotein [a] • cardiovascular • apolipoprotein B-100

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