Objective Macrophages crosstalk with oxidised low-density lipoprotein (oxLDL), play a critical role in the initiation, progression and subsequent stability of atherosclerotic plaques. Statins, inhibitors of HMG CoA (3-hydroxy-3-methylglutaryl coenzyme A) reductase, reduce the expression of inflammatory proteins in addition to their lipid-lowering action. However, the effect and the detailed anti-inflammation mechanisms of statins in macrophages induced by oxLDL remain unclear. In the present study, we investigated the effect of atorvastatin on inflammatory response upon oxLDL stimulation in murine macrophages and analysed the underlying mechanisms.
Methods Raw 264.7 macrophages were cultured and pre-treated with varying doses of atorvastatin in the absence or presence of 40 μg/ml oxLDL. The morphology of the cells was observed and the expression of inflammatory cytokines such as monocyte chemoattractant protein-1 (MCP-1) and tumour necrosis factor (TNF) was assayed by real-time PCR. The expression of Cyclooxygenases -2(COX-2) was performed by real-time PCR and Western blotting. MAPK phosphorylation and IκBa degradation were determined by Western blotting. After pre-incubation with atorvastatin or PD98059, inhibitor of ERK1/2 MAPK, the expression of COX-2 was also detected by real-time PCR and Western blotting.
Results Our findings have shown that exposure of RAW264.7 cells to oxLDL, substantially changed the morphology of the cells and increased the mRNA expression of proinflammatory cytokines and chemokines including TNFa and MCP-1, approximately to 14-fold, 10-fold, respectively while pretreatment with atorvastatin resulted in a significant inhibition of the oxLDL-induced morphological alteration and inflammatory cytokines expression in a dose-dependent fashion. Further investigation of the molecular mechanism revealed that oxLDL upregulated the transcription and protein expression of COX-2 in a time-dependent manner. Moreover, the activation of ERK pathway and IκBa degradation contribute to this effect.
Conclusions Taken together, the anti-inflammatory effect of atorvastatin is mediated through the inhibition of proinflammatory COX-2. Furthermore, suppression of ERK phosphorylation and IκBa degradation is involved in this regulation. Our findings provide novel evidence that statins suppress inflammatory response in murine macrophages induced by oxLDL, exert its anti-atherogenic actions via against inflammation beyond cholesterol-lowering effect.
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