Abstract
Oxidized LDL (oxLDL) promotes lipid accumulation as well as growth and survival signaling in macrophages. OxLDL uptake is mainly due to scavenger receptors SR-AI/II and CD36. However, other scavenger receptors such as lectin-like oxLDL receptor-1 (LOX-1) may also play a role. We used mice with targeted inactivation of the LOX-1 gene to define the role of this receptor in the uptake of oxLDL and in activation of survival pathways. There was no difference in uptake or degradation of 125I-oxLDL in unstimulated macrophages from wild-type and LOX-1 knockout mice and no difference in the rate of clearance of oxLDL from plasma in vivo. However, when expression of LOX-1 was induced with lysophosphatidylcholine, oxLDL uptake and degradation increased 2-fold in wild-type macrophages but did not change in LOX-1 knockout macrophages. Macrophages lacking LOX-1 showed the same stimulation of PKB phosphorylation and enhancement of survival by oxLDL as wild-type cells. These data show that LOX-1 does not alter the uptake of oxLDL in unstimulated macrophages and is not essential for the pro-survival effect of oxLDL in these cells. However, LOX-1 expression is highly inducible by lysophosphatidylcholine and pro-inflammatory cytokines, and if that occurred in macrophages within atheromas, LOX-1 could substantially increase oxLDL uptake by lesion macrophages.
Highlights
Oxidized LDL promotes lipid accumulation as well as growth and survival signaling in macrophages
Other members of this family expressed in macrophages include SRAI/II, CD36, macrosialin/CD68, macrophage receptor with collagenous structure (MARCO), scavenger receptor expressed in endothelial cells (SREC), and a transmembrane chemokine and receptor for phosphatidylserine and Oxidized LDL (oxLDL), SRPSOX/CXCL16 [11]
We previously found that oxLDL promoted survival in SRAI/II-deficient macrophages [31] and in CD36-deficient macrophages, so we hypothesized that like oxLDL receptor-1 (LOX-1) might be the receptor required for PKB activation
Summary
Oxidized LDL (oxLDL) promotes lipid accumulation as well as growth and survival signaling in macrophages. When expression of LOX-1 was induced with lysophosphatidylcholine, oxLDL uptake and degradation increased 2-fold in wild-type macrophages but did not change in LOX-1 knockout macrophages. The lectin-like oxidized LDL receptor (LOX-1) is a 50 kDa type II membrane receptor belonging to the C-type lectin family It is expressed in vascular smooth muscle cells, macrophages, fibroblasts, and platelets [1, 2]. LOX-1 is a member of the scavenger receptor family of multiligand receptors that are thought to play a role in innate immunity [11] Other members of this family expressed in macrophages include SRAI/II, CD36, macrosialin/CD68, macrophage receptor with collagenous structure (MARCO), scavenger receptor expressed in endothelial cells (SREC), and a transmembrane chemokine and receptor for phosphatidylserine and oxLDL, SRPSOX/CXCL16 [11].
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