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 approximately 700 mg/dl, well above the 30 mg/dl threshold associated with increased risk of atherosclerosis in humans; the other had levels of approximately 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.
Schneider
Matthias
M
Gladstone Institute of Cardiovascular Disease, University of California, San Francisco, CA 94158, USA.
Witztum
Joseph L
JL
Young
Stephen G
SG
Ludwig
Erwin H
EH
Miller
Elizabeth R
ER
Tsimikas
Sotirios
S
Curtiss
Linda K
LK
Marcovina
Santica M
SM
Taylor
John M
JM
Lawn
Richard M
RM
Innerarity
Thomas L
TL
Pitas
Robert E
RE
D000818:Animals; D053299:Apolipoprotein B-100; D001055:Apolipoproteins B / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression; D006801:Humans; D017270:Lipoprotein(a) / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D008077:Lipoproteins, LDL / Q000737:chemistry / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D010084:Oxidation-Reduction; D010743:Phospholipids / Q000737:chemistry / Q000378:metabolism*; D019076:Transgenes / Q000235:genetics
D053299:Apolipoprotein B-100; D001055:Apolipoproteins B; D017270:Lipoprotein(a); D008077:Lipoproteins, LDL; D010743:Phospholipids