Abstract 5922: Apolipoprotein C-III Promotes Foam Cell Formation Through the Induction of the Macrophage Scavenger Receptor Lectin-like ox-LDL Receptor 1 (LOX-1)
Background: Clinical studies including our own demonstrated that plasma levels of apoCIII independently predict risk for coronary heart disease. We recently established pre-clinical evidence linking apoCIII to leukocyte-endothelial cell interaction.
Methods/Results: We investigated the direct effects of apoCIII on macrophage foam cell formation, a key contributor to the pathogenesis of atherosclerosis and its acute thrombotic complications. Among major scavenger receptors, clinically relevant concentrations of apoCIII-containing lipoproteins or apoCIII itself, isolated from human plasma, selectively increased LOX-1 expression in human primary macrophages at mRNA (Fig A⇓) and protein levels. ApoCIII promoted macrophage uptake of oxLDL, assessed by direct cellular cholesterol measurement (Fig B⇓) and quantitative Oil Red O staining, an effect that was abolished by siRNA-mediated LOX-1 silencing. Blocking antibody targeting toll like receptor 2 (TLR2) also abolished apoCIII-triggered LOX-1 expression and lipid uptake. In contrast, apoCIII dependent activation of LOX-1 gene promoter increased in HEK293 cells expressing TLR2 compared to 293 cells lacking TLR2 (Fig C⇓), suggesting involvement of this pattern recognition receptor. Finally, intra-peritoneal injection of apoCIII to mice increased lipid accumulation (Fig D–E⇓) and selectively induced LOX-1 expression in peritoneal macrophages in vivo, supporting our in vitro data.
Conclusions: Our study provides the in vitro and in vivo evidence that apoCIII promotes macrophage foam cell formation through activation of LOX-1, offering a critical link between elevated plasma apoCIII levels and coronary events.