25-Hydroxycholesterol promotes vascular calcification via activation of endoplasmic reticulum stress
25-Hydroxycholesterol promotes vascular calcification via activation of endoplasmic reticulum stress
复制标题
25-羟基胆固醇通过激活内质网应激促进血管钙化
DOI：
10.1016/j.ejphar.2020.173165
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发表时间：
2020-08-05
影响因子：
5
通讯作者：
Yan, Jianyun
中科院分区：
文献类型：
--
作者：
Dong, Qianqian;Chen, Yanting;Yan, Jianyun
血管钙化是一个高度调节的过程，类似于血管平滑肌细胞（VSMCs）表型变化的骨生成。25-羟基胆固醇（25-HC）是由胆固醇25-羟化酶合成的氧化固醇之一，已被证明可促进牛钙化血管细胞（CVC）钙化。然而，25-HC是否以及如何调节血管钙化还不完全清楚。在这项研究中，使用血管钙化的体外模型来确定25-HC是否调节血管钙化。茜素红染色和钙含量测定结果表明，25-HC处理促进大鼠和人VSMCs的钙化，并呈剂量依赖性。同样，离体研究进一步证实，25-HC加速大鼠主动脉环钙化。Western blot分析显示25-HC可显著上调VSMCs内质网应激（ERS）信号分子ATF 4和CHOP的表达，流式细胞术分析显示25-HC可促进VSMCs凋亡。此外，通过siRNA敲低CHOP阻断了25-HC诱导的VSMC中的矿物质沉积。总之，本研究首次证明25-HC通过ATF 4/CHOP信号通路促进血管钙化，提示ERS参与了25-HC诱导的血管钙化的调节。
Vascular calcification is a highly regulated process similar to osteogenesis involving phenotypic change of vascular smooth muscle cells (VSMCs). 25-Hydroxycholesterol (25-HC), one of oxysterols synthesized by the enzyme cholesterol 25-hydroxylase, has been shown to promote bovine calcifying vascular cells (CVC) calcification. However, whether and how 25-HC regulates vascular calcification are not completely understood. In this study,in vitroandex vivomodels of vascular calcification were used to determine whether 25-HC regulates vascular calcification. Alizarin red staining and calcium content assay showed that 25-HC treatment promoted calcification of rat and human VSMCs in a dose-dependent manner. Similarly,ex vivostudy further confirmed that 25-HC accelerated calcification of rat aortic rings. In addition, western blot analysis showed that 25-HC significantly up-regulated the expression of endoplasmic reticulum stress (ERS) signaling molecules including ATF4 and CHOP in VSMCs and flow cytometry analysis revealed that 25-HC increased apoptosis of VSMCs. Moreover, knockdown of CHOP by siRNA blocked 25-HC-induced mineral deposition in VSMCs. Collectively, this study for the first time demonstrates that 25-HC promotes vascular calcification via ATF4/CHOP signaling usingin vitroandex vivomodels, suggesting that ERS is involved in the regulation of 25-HC-induced vascular calcification.