Malondialdehyde modification of lipoprotein(a) produces avid uptake by human monocyte-macrophages.
Increased plasma levels of the apoB-100-containing lipoprotein(a) (Lp(a)) are associated with an increased risk for atherosclerosis and myocardial infarction, but the mechanisms by which lipoprotein(a) may accelerate these processes remain obscure. In this study we have investigated the impact of the association of apoprotein(a) with the low density lipoprotein (LDL)-like Lp(a) particle upon specificity of receptor recognition after lipoprotein modification by malondialdehyde or transition metal-induced oxidation. We have determined that radioiodination labels both apoprotein components of Lp(a), that malondialdehyde modification produces an anionic lipoprotein comparable to native Lp(a) in Stokes' radius, and that N,N'-disubstituted 1-amino-3-iminopropene derivatives preferentially cross-link apoprotein(a) to apoB-100 protein. Like LDL, native Lp(a) is recognized in human monocyte-macrophages by the LDL receptor. Like LDL, progressive modification of Lp(a) by malondialdehyde abolishes lipoprotein recognition by the LDL receptor and produces uptake and hydrolysis by the scavenger receptor of human monocyte-macrophages. We propose that intimal retention of Lp(a) by extracellular components of the atherosclerotic reaction places the lipoprotein in a microenvironment favoring subsequent peroxidative modification. The chronic production of lipid peroxide-modified Lp(a) together with unmitigated cellular clearance by scavenger receptors may contribute to the accumulation of lipoprotein-derived lipid in macrophage-derived foam cells of the atherosclerotic reaction.
Haberland
M E
ME
Department of Medicine, School of Medicine, University of California, Los Angeles 90024.
Fless
G M
GM
Scanu
A M
AM
Fogelman
A M
AM
D002478:Cells, Cultured; D003300:Copper / Q000378:metabolism; D004587:Electrophoresis, Agar Gel; D006801:Humans; D007700:Kinetics; D017270:Lipoprotein(a); D008074:Lipoproteins / Q000378:metabolism*; D008077:Lipoproteins, LDL / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism*; D008315:Malondialdehyde / Q000378:metabolism*; D009000:Monocytes / Q000378:metabolism*; D010084:Oxidation-Reduction; D011973:Receptors, LDL / Q000378:metabolism
D017270:Lipoprotein(a); D008074:Lipoproteins; D008077:Lipoproteins, LDL; D011973:Receptors, LDL; D008315:Malondialdehyde; D003300:Copper