Oxidized low-density lipoprotein inhibits the degradation of cyclophilin A via the lysosome in vascular smooth muscle cells

被引:4
作者
Su, Zizhuo [1 ,2 ]
Lin, Maohuan [1 ,2 ]
Su, Yinqing [1 ,2 ]
Li, Jiajie [1 ,2 ]
Lin, Rongjie [1 ,2 ]
Wu, Maoxiong [1 ,2 ]
Wang, Xiaoyu [1 ,2 ]
Huang, Lili [1 ,2 ]
Chen, Yuyang [1 ,2 ]
Shu, Xiaorong [1 ,2 ]
Liang, Shumin [1 ,2 ]
Zhang, Haifeng [1 ,2 ]
Huang, Tucheng [1 ,2 ]
Nie, Ruqiong [1 ,2 ]
Wang, Jingfeng [1 ,2 ]
Xie, Shuanglun [1 ,2 ]
机构
[1] Sun Yat Sen Univ, Sun Yat Sen Mem Hosp, Dept Cardiol, Guangzhou 510120, Guangdong, Peoples R China
[2] Guangdong Prov Key Lab Arrhythmia & Electrophysio, Guangzhou 510120, Guangdong, Peoples R China
来源
AMERICAN JOURNAL OF TRANSLATIONAL RESEARCH | 2020年 / 12卷 / 07期
基金
美国国家科学基金会;
关键词
Oxidized low-density lipoprotein; cyclophilin A; RNA interference; cycloheximide; lysosome; atherosclerotic plaques; AUTOPHAGY; PROTEIN; UBIQUITINATION; MECHANISMS; EMMPRIN;
D O I
暂无
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Background: Cyclophilin A (CyPA) plays an important role in the progression of atherosclerosis. Additionally, it has been reported that lysosomal function is markedly impaired in atherosclerosis induced by oxidized low-density lipoprotein (ox-LDL). As the CyPA degradation pathway remains to be elucidated, we aimed to uncover the role of lysosomes and ox-LDL in the degradation of CyPA. Methods: We exploited RNA interference (RNAi) in combination with either the lysosomal inhibitor chloroquine (CQ) or the proteasomal inhibitor MG-132 to examine CyPA turnover. We also investigated the role of ox-LDL in lysosomal function and the CyPA degradation pathway and determined whether CyPA interacts with the selective autophagy adaptor p62. Results: CQ markedly reversed the CyPA down-regulation induced by RNAi and increased intracellular levels of LC3 and p62. MG-132 significantly suppressed polyubiquitinated protein degradation but did not inhibit RNAi-induced CyPA downregulation. Additionally, neither CQ nor MG-132 influenced the gene-silencing efficiency of CyPA siRNA. Moreover, ox-LDL induced cytosolic accu-mulation of p62 was inconsistent with increased expression of LC3-II. Meanwhile, ox-LDL inhibited RNAi-induced downregulation of CyPA. Immunofluorescence indicated colocalization of endogenous CyPA with ubiquitin and with p62 in response to CQ treatment, and co-immunoprecipitation analysis confirmed interaction between CyPA and p62. Conclusion: CyPA is degraded by a lysosome-dependent pathway that may involve p62-mediated selective autophagy. Furthermore, ox-LDL modulates the degradation of CyPA via its inhibitory role in lysosomes, contributing to increased expression of CyPA in atherosclerotic plaques.
引用
收藏
页码:3964 / 3973
页数:10
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