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

Abstract

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 CuSO(4) 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 CuSO(4) 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 CuSO(4) 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 CuSO(4) 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.

Curcumin Alleviates oxLDL Induced MMP-9 and EMMPRIN Expression through the Inhibition of NF-κB and MAPK Pathways in Macrophages

“…In the present study, our results showed that curcumin significantly reduced MMP-9 and EMMPRIN expression under the stimulation of oxLDL in macrophages, which means that curcumin could be a potential therapeutic agent for inhibiting plaque rupture or retarding atherosclerosis. oxLDL increased EMMPRIN and MMP-9 expression through NF-κB and p38 MAPK pathways and the role of elevated NF-κB and p38 MAPK activity in oxLDL induced atherosclerotic plaque rupture was previous demonstrated (Kojima et al, 2010 ; Yi et al, 2012 ), which is in agreement with other studies (Kim et al, 2001 ; Xie et al, 2011 ; Radhika and Sudhakaran, 2013 ). Results presented here indicated that NF-κB and p38 MAPK is constitutively active in oxLDL stimulated macrophages.…”

H2 Inhibits the Formation of Neutrophil Extracellular Traps

“…HOCl-modified low-density lipoprotein leads to unregulated uptake of oxidized low-density lipoprotein into macrophages, followed by their differentiation into foamy macrophages. 57 HOCl oxidizes cardiac myoglobin, which may cause cardiac inflammation and dysfunction in mice after myocardial infarction (MI). 58 HOCl is also shown to have a profound adverse effect on left ventricular remodeling and function after MI.…”

Combining use of Phillyrin and autophagy blocker alleviates laryngeal squamous cell carcinoma via AMPK/mTOR/p70S6K signaling

“…Therefore, using 3-MA might have a slight increase in autophagy [35]. To be more clear, we additionally used another autophagy inhibitor CQ, a lysosomal degradation blocker, which could inhibit the fusion of autophagosomes and lysosomes [36,37]. We believe that 3-MA and CQ are more illustrative for our conclusions.…”