Li Yanqing, Li Yuqing, Li Ying, Yang Ziyuan, Geng Haigang, Liu Chenxi, Hao Wei, Yang Rui, Jin Sheng, Wu Yuming, Wang Xiaoning, Teng Xu
Hebei Provincial Hospital of Chinese Medicine, Hebei University of Chines Medicine, Shijiazhuang 050011, China.
Department of Physiology, Hebei Medical University, Shijiazhuang 050017, China.
J Mol Cell Cardiol. 2021 Mar;152:17-28. doi: 10.1016/j.yjmcc.2020.11.017. Epub 2020 Dec 3.
Apelin is the endogenous ligand of G protein-coupled receptor APJ and play an important role in the regulation of cardiovascular homeostasis. We aimed to investigate whether apelin ameliorates vascular calcification (VC) by inhibition of endoplasmic reticulum stress (ERS).
VC model in rats was induced by nicotine plus vitamin D, while calcification of vascular smooth muscle cell (VSMC) was induced by beta-glycerophosphate. Alizarin Red S staining showed dramatic calcium deposition in the aorta of rats with VC, while calcium contents and ALP activity also increased in calcified aorta. Protein levels of apelin and APJ were decreased in the calcified aorta. In rats with VC, apelin treatment significantly ameliorated aortic calcification, compliance and stimulation of ERS. The ameliorative effect of apelin on VC and ERS was also observed in calcified VSMCs. ERS stimulator (tunicamycin or DTT) blocked the beneficial effect of apelin. Apelin treatment activated the PI3K/Akt signaling, blockage of which by wortmannin or inhibitor IV prevented the ameliorative effect of apelin, while ERS inhibitor 4-PBA rescued the blockade effect of wortmannin. Akt-induced GSK inhibition prevented the phosphorylation of PERK and IRE1, and the activation of these two major ERS branches. F13A blocked the ameliorative effect of apelin on VC and ERS, which was reversed by treatment with 4-PBA or Akt activator SC79 CONCLUSIONS: Apelin ameliorated VC by binding to APJ and then prevented ERS activation by stimulating Akt signaling. These results might provide new target for therapy and prevention of VC.
Apelin是G蛋白偶联受体APJ的内源性配体，在心血管稳态调节中起重要作用。我们旨在研究Apelin是否通过抑制内质网应激（ERS）来改善血管钙化（VC）。
尼古丁加维生素D诱导大鼠VC模型，β-甘油磷酸诱导血管平滑肌细胞（VSMC）钙化。茜素红S染色显示VC大鼠主动脉有大量钙沉积，钙化主动脉中钙含量和碱性磷酸酶（ALP）活性也增加。钙化主动脉中Apelin和APJ的蛋白水平降低。在VC大鼠中，Apelin治疗显著改善主动脉钙化、顺应性并抑制ERS。在钙化的VSMC中也观察到Apelin对VC和ERS的改善作用。ERS刺激剂（衣霉素或二硫苏糖醇）阻断了Apelin的有益作用。Apelin治疗激活了PI3K/Akt信号通路，渥曼青霉素或抑制剂IV阻断该通路可阻止Apelin的改善作用，而ERS抑制剂4-苯基丁酸（4-PBA）可挽救渥曼青霉素的阻断作用。Akt诱导的糖原合成酶激酶（GSK）抑制可阻止蛋白激酶R样内质网激酶（PERK）和肌醇需求酶1（IRE1）的磷酸化以及这两个主要ERS分支的激活。F13A阻断了Apelin对VC和ERS的改善作用，用4-PBA或Akt激活剂SC79治疗可逆转这种作用。结论：Apelin通过与APJ结合，然后通过刺激Akt信号通路阻止ERS激活来改善VC。这些结果可能为VC的治疗和预防提供新靶点。
