High-level lipoprotein [a] expression in transgenic mice: evidence for oxidized phospholipids in lipoprotein [a] but not in low density lipoproteins

Journal of Lipid Research

Santica M. Marcovina¹  Robert E. Pitas²  Joseph L. Witztum²  Elizabeth R. Miller³  Sotirios Tsimikas⁴  Stephen G. Young⁵  Erwin H. Ludwig⁶  John M. Taylor⁷  Linda K. Curtiss⁸  Richard M. Lawn⁹  Thomas L. Innerarity^1,10  Matthias Schneider^1,10 

[1] CV Therapeutics, Palo Alto, CA 94304;Cardiovascular Research Institute, 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 Medicine, University of California, San Diego, La Jolla, CA 92093;Department of Medicine, University of California, San Francisco, CA 94158;Department of Pathology, University of California, San Francisco, CA 94158;Department of Physiology, University of California, San Francisco, CA 94158;Gladstone Institute of Neurological Disease, University of California, San Francisco, CA 94158;Gladstone Institute of Cardiovascular Disease, University of California, San Francisco, CA 94158;

关键词: atherosclerosis;    oxidized low density lipoprotein;    apolipoprotein [a];    cardiovascular;    apolipoprotein B-100;   

DOI  :  

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown