Inhibitory Effects of Simvastatin on Oxidized Low-Density Lipoprotein-lnduced Endoplasmic Reticulum Stress and Apoptosis in Vascular Endothelial Cells

作     者：Guo-Qiang Zhang Yong-Kang Tao Yong-Ping Bai Sheng-Tao Yan Shui-Ping Zhao Zhang Guo-Qiang;Tao Yong-Kang;Bai Yong-Ping;Yan Sheng-Tao;Zhao Shui-Ping

作者机构：Department of Emergency China-Japan Friendship Hospital Beijing 100029 China Department of Geriatric Medicine Xiangya Hospital Central South University Changsha Hunan 410008 China Department of Cardiology The Second Xiangya Hospital Central South University Changsha Hunan 410011 China 

出 版 物：《Chinese Medical Journal》 (中华医学杂志（英文版）)

年 卷 期：2018年第131卷第8期

页      面：950-955页

核心收录：

学科分类：0710[理学-生物学] 1002[医学-临床医学] 07[理学] 071009[理学-细胞生物学] 0713[理学-生态学] 

基　　金：support and sponsorship This study was supported by a grant from the State Key Clinical Specialty Construction Project Funding China 

主　　题：Apoptosis Endoplasmic Reticulum Stress Endothelial Cells Oxidized Low-Density Lipoprotein Simvastatin 

摘      要：Background：Oxidized low-density lipoprotein （ox-LDL）-induced oxidative stress and endothelial apoptosis are essential for atherosclerosis. Our previous study has shown that ox-LDL-induced apoptosis is mediated by the protein kinase RNA-like endoplasmic reticulum kinase （PERK）/eukaryotic translation initiation factor 2α-subunit （eIF2α）/CCAAT/enhancer-binding protein homologous protein （CHOP） endoplasmic reticulum （ER） stress pathway in endothelial cells. Statins are cholesterol-lowering drugs that exert pleiotropic effects including suppression of oxidative stress. This study aimed to explore the roles of simvastatin on ox-LDL-induced ER stress and apoptosis in endothelial cells.Methods：Human umbilical vein endothelial cells （HUVECs） were treated with simvastatin （0.1, 0.5, or 2.5 μmol/L） or DEVD-CHO （selective inhibitor of caspase-3, 100 μmol/L） for 1 h before the addition of ox-LDL （100 μg/ml） and then incubated for 24 h, and untreated cells were used as a control group. Apoptosis, expression of PERK, phosphorylation of eIF2α, CHOP mRNA level, and caspase-3 activity were measured. Comparisons among multiple groups were performed with one-way analysis of variance （ANOVA） followed by post hoc pairwise comparisons using Tukey’s tests. A value of P 〈 0.05 was considered statistically significant.Results：Exposure of HUVECs to ox-LDL resulted in a significant increase in apoptosis （31.9% vs. 4.9%, P 〈 0.05）. Simvastatin （0.1, 0.5, and 2.5 μmol/L） led to a suppression of ox-LDL-induced apoptosis （28.0%, 24.7%, and 13.8%, F = 15.039, all P 〈 0.05, compared with control group）. Ox-LDL significantly increased the expression of PERK （499.5%, P 〈 0.05） and phosphorylation of eIF2α （451.6%, P 〈 0.05）, if both of which in the control groups were considered as 100%. Simvastatin treatment （0.1, 0.5, and 2.5 μmol/L） blunted ox-LDL-induced expression of PERK （407.8%, 339.1%, and 187.5%, F = 10.121, all P 〈 0.05, compared with control group） and phosphorylation of eIF2α （407.8%, 339.1%, 187.5%, F = 11.430, all P 〈 0.05, compared with control group）. In contrast, DEVD-CHO treatment had no significant effect on ox-LDL-induced expression of PERK （486.4%） and phosphorylation of eIF2α （418.8%）. Exposure of HUVECs to ox-LDL also markedly induced caspase-3 activity together with increased CHOP mRNA level; these effects were inhibited by simvastatin treatment. Conclusions：This study suggested that simvastatin could inhibit ox-LDL-induced ER stress and apoptosis in vascular endothelial cells.