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.

中文翻译：

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oxLDL /β2GPI/抗β2GPI复合物的双相效应对VSMC增殖和凋亡的影响。

在我们之前的研究中，证明了oxLDL /β2GPI/抗β2GPI复合物通过TLR4 /NF-κB途径进一步增强了VSMC的泡沫细胞形成和迁移以及炎性细胞因子的表达。但是，关于oxLDL /β2GPI/抗β2GPI复合物的其他促动脉粥样硬化致病作用（例如对增殖和凋亡的影响）的信息稀少。在本研究中，我们集中于oxLDL /β2GPI/anti-β2GPI复合物对VSMC生存的双相作用及其潜在机制。数据显示，短时暴露于oxLDL /β2GPI/抗β2GPI复合物可以激活NF-κB和ERK1 / 2途径并刺激VSMC中的细胞增殖。相反，更长的暴露时间增加了p38途径激活和细胞凋亡的水平。此外，oxLDL /β2GPI/抗β2GPI复合物对增殖和凋亡以及信号通路激活的促进作用均强于其他对照组。选择性阻滞剂的使用表明TLR4 /NF-κB和ERK1 / 2部分介导了oxLDL /β2GPI/抗β2GPI复合物诱导的增殖，并对复合物刺激的细胞凋亡具有抑制作用。相反，TLR2 / p38部分介导oxLDL /β2GPI/抗β2GPI复合物诱导的细胞凋亡，并对复合物刺激的增殖产生负面影响。特定的NF-κB和ERK1 / 2活化抑制剂可以增强oxLDL /β2GPI/抗β2GPI复合物诱导的p38磷酸化，反之亦然。经过NADPH氧化酶抑制剂的预处理，证实细胞内ROS的产生参与了oxLDL /β2GPI/anti-β2GPI复合物诱导的增殖和凋亡，以及NF-κB和MAPK的磷酸化。综上所述，我们的数据清楚地表明，oxLDL /β2GPI/抗β2GPI复合物对VSMC生存具有双相影响，部分由ROS诱导的NF-κB和MAPKs激活介导。TLR4 /NF-κB和TLR2 / p38通路在这种双重效应引发的信号网络中起辅助作用，并且NF-κB，ERK1 / 2和p38的磷酸化之间存在权衡关系。oxLDL /β2GPI/抗β2GPI复合物对VSMC存活的双重作用有助于形成动脉粥样硬化病变的典型结构，尤其是局部过度生长和坏死。部分由ROS诱导的NF-κB和MAPKs激活介导。TLR4 /NF-κB和TLR2 / p38通路在这种双重效应引发的信号网络中起辅助作用，并且NF-κB，ERK1 / 2和p38的磷酸化之间存在权衡关系。oxLDL /β2GPI/抗β2GPI复合物对VSMC存活的双重作用有助于形成动脉粥样硬化病变的典型结构，尤其是局部过度生长和坏死。部分由ROS诱导的NF-κB和MAPKs激活介导。TLR4 /NF-κB和TLR2 / p38通路在这种双重效应引发的信号网络中起辅助作用，并且NF-κB，ERK1 / 2和p38的磷酸化之间存在权衡关系。oxLDL /β2GPI/抗β2GPI复合物对VSMC存活的双重作用有助于形成动脉粥样硬化病变的典型结构，尤其是局部过度生长和坏死。