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

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.