The biphasic effects of the oxLDL/β2GPI/anti-β2GPI complex on VSMC proliferation and apoptosis

Abstract

In our previous study, the oxLDL/β2GPI/anti-β2GPI complex was demonstrated to further enhance the foam cell formation and migration of VSMC, as well as the expression of inflammatory cytokines, via the TLR4/NF-κB pathway. However, sparse information is available on other pro-atherogenic pathogenic effects of the oxLDL/β2GPI/anti-β2GPI complex, such as effects on proliferation and apoptosis. In the present study, we focused on the biphasic effects and underlying mechanisms of the oxLDL/β2GPI/anti-β2GPI complex on VSMC survival. The data showed that short exposure to the oxLDL/β2GPI/anti-β2GPI complex could activate NF-κB and ERK1/2 pathways and stimulate cell proliferation in VSMC. In contrast, longer exposure increased the level of p38 pathway activation and cell apoptosis. Additionally, the promotion effect of the oxLDL/β2GPI/anti-β2GPI complex on both proliferation and apoptosis, as well as signaling pathway activation, was stronger than that of the other control groups. The use of selective blockers showed that TLR4/NF-κB and ERK1/2 partly mediated oxLDL/β2GPI/anti-β2GPI complex-induced proliferation and had an inhibitory effect on complex-stimulated apoptosis. Conversely, TLR2/p38 partly mediated oxLDL/β2GPI/anti-β2GPI complex-induced apoptosis and had a negative effect on complex-stimulated proliferation. Specific inhibitors of NF-κB and ERK1/2 activation could augment the oxLDL/β2GPI/anti-β2GPI complex-induced phosphorylation of p38 and vice versa. Under pretreatment with NADPH oxidase inhibitors, intracellular ROS generation was confirmed to participate in oxLDL/β2GPI/anti-β2GPI complex-induced proliferation and apoptosis, as well as the phosphorylation of NF-κB and MAPKs. Taken together, our data clearly revealed that the oxLDL/β2GPI/anti-β2GPI complex had biphasic effects on VSMC survival, partly mediated by ROS-induced NF-κB and MAPKs activation. The TLR4/NF-κB and TLR2/p38 pathways played supporting roles in this dual effects-initiated signal network, and there is a trade-off relationship between the phosphorylation of NF-κB, ERK1/2 and p38. The dual effects of the oxLDL/β2GPI/anti-β2GPI complex on VSMC survival contribute to the development of the structure typical of atherosclerotic lesions, particularly focal excessive growth alternating with necrosis.