Upregulation of macrophage-specific functions by oxidized LDL: lysosomal degradation-dependent and -independent pathways

作者：Radhika A; Sudhakaran P R^*

来源：Molecular and Cellular Biochemistry, 2013, 372(1-2): 181-190.

DOI：10.1007/s11010-012-1459-8

• oxLDL
• Monocyte-macrophage
• PPAR-gamma
• NF kappa B
• AP-1
• ERK 1/2
• p38 MAPK
• Akt
• Lysosomal degradation

Formation of foam cells from macrophages, which are formed by the differentiation of blood-borne monocytes, is a critical early event in atherogenesis. To examine how pre-exposure of monocytes to modified proteins, such as oxLDL, influences their differentiation to macrophages, an in vitro model system using isolated PBMC maintained in culture in the presence of oxLDL was used. Pretreatment of monocytes with oxLDL caused a faster rate of expression of macrophage-specific functions and loss of monocyte-specific functions compared to unmodified LDL. The effect of oxidation of lipid component of LDL by CuSO4 and its protein component by HOCl, on mo-mI center dot differentiation was studied by monitoring the upregulation of macrophage-specific functions, particularly MMP-9. Chloroquine, a lysosomal degradation blocker, significantly reversed the effect mediated by CuSO4 oxLDL, indicating the involvement of lysosomal degradation products, while no such effect was observed in HOCl oxLDL-treated cells, indicating the existence of a pathway independent of its lysosomal degradation products. Reversal of the effect of oxLDL by NAC and Calphostin C, an inhibitor of PKC, suggested the activation of RO-mediated signaling pathways. Use of inhibitors of signaling pathways showed that CuSO4 oxLDL upregulated mI center dot-specific MMP-9 through p38 MAPK and Akt-dependent pathways, while HOCl oxLDL utilized ERK A1/2 and Akt. Further analysis showed the activation of PPAR gamma and AP-1 in CuSO4 oxLDL, while HOCl-oxLDL-mediated effect involved NF kappa B and AP-1. These results suggest that lipid oxLDL- and protein oxLDL-mediated upregulation of mo-mI center dot-specific functions involve lysosomal degradation-dependent and -independent activation of intracellular signaling pathways.

• 出版日期2013-1