Macrophage foam cell lipoprotein(a)/apoprotein(a) receptor. Cell-surface localization, dependence of induction on new protein synthesis, and ligand specificity.

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Abstract
Understanding the interaction of the atherogenic lipoprotein, lipoprotein(a) [Lp(a)], with macrophages may provide important insight into the physiology and pathophysiology of this lipoprotein. We have recently shown that cholesterol loading of macrophages, such as occurs in atheroma foam cells, leads to marked upregulation of a novel receptor activity for native Lp(a) and its plasminogen-like protein component, apoprotein(a) [apo(a)]. We show here that the Lp(a)/apo(a) receptor activity on cholesterol-loaded macrophages is trypsin sensitive, indicating that a cell-surface protein is involved and that the upregulation by cholesterol loading requires new protein synthesis. Ligand studies revealed that the foam cell receptor activity recognizes Lp(a) containing both small and large isoforms of apo(a) as well as rhesus monkey Lp(a), which contains an inactive kringle-4(37) (K4(37) lysine-binding domain. Elastase degradation products of plasminogen did not compete for 125I-labeled recombinant apo(a) [125I-r-apo(a)] internalization and degradation by foam cells, indicating that the K4(37) sequence, as well as the K5 and "protease" domains of apo(a), are not sufficient for receptor interaction. Consistent with these data, the degradation of 125I-r-apo(a) was completely blocked by an anti-Lp(a) polyclonal antibody that does not cross-react with plasminogen. Furthermore, the multiple sialic residues of apo(a) are also not involved in receptor interaction, since desialylated r-apo(a) interacted with foam cells as well as native r-apo(a). In contrast, reduced and denatured r-apo(a) was degraded by foam cells only slightly better than by control cells [28% increased degradation by foam cells versus 450% for native r-apo(a)], suggesting that the upregulated receptor activity recognizes certain secondary and tertiary structural features of apo(a).(ABSTRACT TRUNCATED AT 250 WORDS)