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

ABSTRACT: 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 downregulation 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 accumulation 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.

SUBMITTER: Su Z

PROVIDER: S-EPMC7407676 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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

Su Zizhuo Z Lin Maohuan M Su Yinqing Y Li Jiajie J Lin Rongjie R Wu Maoxiong M Wang Xiaoyu X Huang Lili L Chen Yuyang Y Shu Xiaorong X Liang Shumin S Zhang Haifeng H Huang Tucheng T Nie Ruqiong R Wang Jingfeng J Xie Shuanglun S

American journal of translational research 20200715 7

<h4>Background</h4>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.<h4>Methods</h4>We exploited RNA interference (RNAi) in combination with either the lysosomal inhibitor ch ...[more]

PMID: 32774749

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Project description:Atherosclerosis is a disease during which the inside of an artery narrows due to the accumulation of plaque, and vascular smooth muscle cells (VSMCs) are involved in the progression of atherosclerosis. Circular RNAs (circRNAs) have been reported to be involved in the progression of atherosclerosis. However, the role of circ_0010283 in atherosclerosis progression remains unclear. The present study aimed to investigate the functions and the mechanism of circ_0010283 in oxidized low‑density lipoprotein (ox‑LDL)‑induced VSMCs and to identify new potential biomarkers for the treatment of atherosclerosis. Cell viability and migration were examined by 3‑(4,5‑dimethylthiazol‑2‑yl)‑2,5‑diphenyltetrazolium bromide and Transwell assays. The relationship between microRNA (miR)‑370‑3p and circ_0010283 or high mobility group box 1 (HMGB1) was predicated by online software and confirmed by dual‑luciferase reporter assay and RNA immunoprecipitation assay. The results of the present study demonstrated that the expression levels of circ_0010283 and HMGB1 were significantly upregulated in ox‑LDL‑induced VSMCs compared with those in VSMCs without ox‑LDL induction, whereas the expression of miR‑370‑3p was downregulated. Knockdown of circ_0010283 suppressed VSMC viability and migration, as well as the expression of viability‑associated proteins cyclin D1 and proliferating cell nuclear antigen, and migration‑associated proteins matrix metalloproteinase 2 (MMP2) and MMP9 in ox‑LDL‑induced VSMCs compared with untreated VSMCs. In addition, miR‑370‑3p was demonstrated to be a target of circ_0010283 and to target HMGB1; thus, circ_0010283 regulated HMGB1 expression via miR‑370‑3p. Further experiments indicated that inhibition of miR‑370‑3p reversed the circ_0010283 silencing‑mediated inhibitory effects on VMSC viability and migration. Additionally, the miR‑370‑3p‑mediated suppressive effects on cell viability and migration were rescued by overexpression of HMGB1. In conclusion, circ_0010283 mediated cell viability and migration via a miR‑370‑3p/HMGB1 axis in ox‑LDL‑induced VSMCs.

Dataset Information

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

Publications

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

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