ERK5/KLF2 activation is involved in the reducing effects of puerarin on monocyte adhesion to endothelial cells and atherosclerotic lesion in apolipoprotein E-deficient mice
ERK5/KLF2 activation is involved in the reducing effects of puerarin on monocyte adhesion to endothelial cells and atherosclerotic lesion in apolipoprotein E-deficient mice
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ERK5/KLF2 激活参与葛根素降低载脂蛋白 E 缺陷小鼠单核细胞与内皮细胞粘附和动脉粥样硬化病变的作用
DOI：
10.1016/j.bbadis.2018.04.021
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发表时间：
2018-08-01
影响因子：
6.2
通讯作者：
Ou, Hailong
中科院分区：
文献类型：
--
作者：
Deng, Yan;Lei, Tingwen;Ou, Hailong
葛根素具有抗氧化和抗炎特性，已被证明对动脉粥样硬化和其他心血管疾病具有保护作用。然而，详细的分子机制仍不清楚。在这里，我们确定葛根素的动脉粥样硬化保护作用是否是通过减少单核细胞粘附来实现的，并探讨了其潜在机制。结果显示，葛根素剂量和时间依赖性地降低oxLDL诱导的单核细胞THP-1对HUVEC的粘附以及HUVEC中粘附相关基因如VCAM-1、ICAM-1、MCP-1和IL-8的表达。葛根素激活 ERK5 磷酸化并上调下游 KLF2 及其靶基因内皮一氧化氮合酶和血栓调节蛋白的表达。然而，保护作用被 ERK5/KLF2 通路抑制剂 XDM8-92、BIX02189 或 KLF2 siRNA 逆转，表明该通路参与了该功能。离体测定中，THP-1 与接受各种治疗的 apoE-/- 小鼠分离的内皮细胞粘附，进一步证实了 HUVEC 的结果。最后，我们发现，与仅接受高脂饮食（HFD）的小鼠相比，接受葛根素治疗的高脂饮食（HFD）小鼠主动脉根部和整个主动脉两个横截面的动脉粥样硬化病变均显着减少，但在XMD8-92组中分别增加了76％和71％，在BIX02189组中分别增加了82％和73％。总之，数据表明，葛根素在体外和体内抑制单核细胞粘附，从而减少 apoE-/- 小鼠的动脉粥样硬化病变。保护作用是通过激活ERK5/KLF2信号通路介导的。我们的研究结果增进了对葛根素在动脉粥样硬化中的功能的理解，并指出了预防该疾病的方法。
Puerarin has properties of anti-oxidation and anti-inflammation, which has been demonstrated protective effects in atherosclerosis and other cardiovascular diseases. However, the detail molecular mechanism still remains unclear. Here, we determined whether the atheroprotective effect of puerarin was by reducing monocyte adhesion and explored the underlying mechanism. The results showed that puerarin dose- and time-dependently reduced oxLDL-induced monocyte THP-1 adhesion to HUVECs and the expression of adhesion-related genes such as VCAM-1, ICAM-1, MCP-1 and IL-8 in HUVECs. Puerarin activated ERK5 phosphorylation and up-regulated expressions of downstream KLF2 and its targeted genes endothelial nitric oxide synthase and thrombomodulin. However, the protective effects were reversed by ERK5/KLF2 pathway inhibitor XDM8-92, BIX02189 or KLF2 siRNA suggesting the pathway involved in the function. The ex vivo assay, in which THP-1 adhesion to endothelium isolated from apoE-/- mice received various treatments further confirmed the results from HUVECs. Finally, we found that the atherosclerotic lesions in both cross sections at aortic root and whole aorta were significantly reduced in high fat-diet (HFD) mice with puerarin treatment compared with the HFD-only mice, but were increased respectively by 76% and 71% in XMD8-92 group, and 82% and 73% in BIX02189 group. Altogether, the data revealed that puerarin inhibited the monocyte adhesion in vitro and in vivo and thus reduced atherosclerotic lesions in apoE-/- mice; the protective effects were mediated by activation of ERK5/KLF2 signaling pathway. Our findings advance the understanding of puerarin function in atherosclerosis and point out a way to prevent the disease.