Molecular and Cellular Biochemistry

, Volume 372, Issue 1–2, pp 181–190 | Cite as

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

  • A. Radhika
  • P. R. Sudhakaran


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–mϕ 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 mϕ-specific MMP-9 through p38 MAPK and Akt-dependent pathways, while HOCl oxLDL utilized ERK ½ and Akt. Further analysis showed the activation of PPARγ and AP-1 in CuSO4 oxLDL, while HOCl–oxLDL-mediated effect involved NFκB and AP-1. These results suggest that lipid oxLDL- and protein oxLDL-mediated upregulation of mo–mϕ-specific functions involve lysosomal degradation-dependent and -independent activation of intracellular signaling pathways.


oxLDL Monocyte–macrophage PPAR-γ NFκB AP-1 ERK ½ p38 MAPK Akt Lysosomal degradation 



Financial assistance received from the Indian Council of Medical Research to A. Radhika in the form of SRF is gratefully acknowledged.


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Copyright information

© Springer Science+Business Media New York 2012

Authors and Affiliations

  1. 1.Department of BiochemistryUniversity of KeralaKariavattom, TrivandrumIndia
  2. 2.Inter-University Centre of Excellence in Bioinformatics, Department of Computational Biology & BioinformaticsUniversity of KeralaKariavattom, ThiruvananthapuramIndia

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