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

被引:46
作者
Schneider, M
Witztum, JL
Young, SG
Ludwig, EH
Miller, ER
Tsimikas, S
Curtiss, LK
Marcovina, SM
Taylor, JM
Lawn, RM
Innerarity, TL
Pitas, RE [1 ]
机构
[1] Univ Calif San Francisco, Gladstone Inst Cardiovasc Dis, San Francisco, CA 94158 USA
[2] Univ Calif San Francisco, Cardiovasc Res Inst, San Francisco, CA 94158 USA
[3] Univ Calif San Diego, Dept Med, La Jolla, CA 92093 USA
[4] Univ Calif San Francisco, Dept Med, San Francisco, CA 94158 USA
[5] Scripps Res Inst, Dept Immunol, La Jolla, CA 92037 USA
[6] Univ Washington, Dept Med, NW Lipid Res Labs, Seattle, WA 98103 USA
[7] Univ Calif San Francisco, Dept Physiol, San Francisco, CA 94158 USA
[8] CV Therapeut, Palo Alto, CA 94304 USA
[9] Univ Calif San Francisco, Dept Pathol, San Francisco, CA 94158 USA
[10] Univ Calif San Francisco, Gladstone Inst Neurol Dis, San Francisco, CA 94158 USA
关键词
atherosclerosis; oxidized low density lipoprotein; apolipoprotein [a; cardiovascular; apolipoprotein B-100;
D O I
10.1194/jlr.M400467-JLR200
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
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 similar to 700 mg/dl, well above the 30 mg/dl threshold associated with increased risk of atherosclerosis in humans; the other had levels of similar to 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.
引用
收藏
页码:769 / 778
页数:10
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