Iron-dependent lysosomal LDL oxidation induces the expression of scavenger receptor A in human THP-1 monocytes.

Abstract

Atherosclerosis leading to cardiovascular diseases remains a dominant medical problem. In the early stages of this disease, the interaction between circulating monocytes and the endothelium is crucial. Monocytes and macrophages express scavenger receptor A (SR-A), which mediates cell adhesion and subsequently uptake of oxidized low-density lipoproteins (LDL). High iron stores in monocytes or macrophages are known to predispose individuals to atherosclerosis, however the reasons remain poorly understood. We hypothesized that a combination of iron and LDL may induce proatherogenic changes in circulating monocytes. Here, we treated a human monocytic cell line THP-1 with isolated LDL and/or iron. A limited uptake of native LDL, but not iron or oxidized LDL, markedly induced expression of SR-A in these cells. Both SR-AI and SR-AII isoforms were upregulated. The increased SR-A was also seen at the protein level, and LDL treatment increased cellular adhesion. The induction of SR-A by LDL was inhibited by the lysosomotropic thiol WR-1065 and by the chain-breaking lipophilic antioxidant butylated hydroxytoluene (BHT). The fluorescent probe BODIPY C11 exhibited increased lipid peroxidation inside lysosomes after LDL administration. The induction of SR-A by LDL was blocked by two silencing RNAs directed against the nuclear coactivator receptor NCOA4, the cargo receptor necessary for the autophagy of ferritin. These results may point to a new pathogenetic mechanism of early-stage atherosclerosis, in which high iron stores in circulating monocytes, through increased lysosomal lipid peroxidation, may lead to an upregulated expression of SR-A, which makes the cells more adhesive and hence more atherogenic.