Pro?atherogenic activation of A7r5 cells induced by the oxLDL/β2GPI/anti?β2GPI complex

摘要

A previous study has revealed that oxidized low?density lipoprotein (oxLDL)/β2?glycoprotein I (β2GPI)/anti?β2?glycoprotein I (anti?β2GPI), an immune complex, is able to activate the Toll?like receptor 4 (TLR4)uclear factor κβ (NF?κβ) inflammatory signaling pathway in macrophages, and consequently enhance foam cell formation and the secretion of prothrombin activators. However, the effects of the oxLDL/β2GPI/anti?β2GPI complex on vascular smooth muscle cells have yet to be investigated. The present study investigated whether the oxLDL/β2GPI/anti?β2GPI complex was able to reinforce the pro?atherogenic activities of a rat thoracic aorta smooth muscle cell line (A7r5) and examined the underlying molecular mechanisms. The results revealed that the oxLDL/β2GPI/anti?β2GPI complex treatment significantly (P<0.05 vs. the media, oxLDL, oxLDL/β2GPI and β2GPI/anti?β2GPI groups) enhanced the pro?atherogenic activation of A7r5 cells, including intracellular lipid loading, Acyl?coenzyme A cholesterol acyltransferase mRNA expression, migration, matrix metalloproteinase?9 and monocyte chemoattractant protein 1 secretion, all via TLR4. In addition, the expression of TLR4 and the phosphorylation of NF?κβ p65, p38 and ERK1/2 were also upregulated in oxLDL/β2GPI/anti?β2GPI complex?treated A7r5 cells. Pre?treatment with TAK?242, a TLR4 inhibitor, was able to partly attenuate the oxLDL/β2GPI/anti?β2GPI complex?induced phosphorylation of NF?κβ p65; however, it had no effect on the phosphorylation of extracellular regulated kinase 1/2 (ERK1/2) and p38. Meanwhile, the NF?κβ p65 inhibitor ammonium pyrrolidinedithiocarbamate and the ERK1/2 inhibitor U0126, but not the p38 inhibitor SB203580, were able to block oxLDL/β2GPI/anti?β2GPI complex?induced foam cell formation and migration in A7r5 cells. Hence, it was demonstrated that the oxLDL/β2GPI/anti?β2GPI complex is able to enhance the lipid uptake, migration and active molecule secretion of A7r5 cells via TLR4, and finally deteriorate atherosclerosis plaques. Additionally, it was demonstrated that oxLDL/β2GPI/anti?β2GPI complex?induced foam cell formation and migration may be partly mediated by the TLR4/NF?κβ signaling pathway and that ERK1/2 may also participate in the process.