Institute of Cardiovascular Disease, Key Laboratory for Arteriosclerology of Hunan Province, Hunan International Scientific and Technological Cooperation Base of Arteriosclerotic Disease, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, China.
Institute of Cardiovascular Disease, Key Laboratory for Arteriosclerology of Hunan Province, Hunan International Scientific and Technological Cooperation Base of Arteriosclerotic Disease, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, China.; Institute of Pharmacy & Pharmacology, University of South China, Hengyang, Hunan 421001, China.
Biochim Biophys Acta Mol Cell Biol Lipids. 2021 May;1866(5):158904. doi: 10.1016/j.bbalip.2021.158904. Epub 2021 Feb 10.
OBJECTIVE: The purpose of this study was to explore the role of long noncoding RNA (lncRNA) prostate cancer antigen 3 (PCA3) in atherosclerosis and the underlying mechanism. METHODS: The Gene Expression Omnibus (GEO) datasets were used to divide differentially expressed lncRNAs, microRNAs (miRNAs), and mRNAs. The expression of PCA3, miR-140-5p, RFX7 and ABCA1 were determined by qPCR or Western blot in ox-LDL-treated macrophages. Macrophage lipid accumulation s was evaluated using the Oil Red O staining and high-performance liquid chromatography. Target relationships among PCA3, miR-140-5p, RFX7, and ABCA1 promoter area were validated via dual-luciferase reporter gene assay or chromatin immunoprecipitation assay. The apoE mouse model in vivo was designed to evaluate the effect of PCA3 on the reverse cholesterol transport (RCT) and atherosclerosis. RESULTS: PCA3 was down-regulated in foam cells, whereas miR-140-5p was highly expressed. Overexpression of PCA3 promoted ABCA1-mediated cholesterol efflux and reduced lipid accumulation in macrophages. Besides, RFX7 bound to the ABCA1 promoter and increased ABCA1 expression. Targeted relationships and interactions on the expression between miR-140-5p and PCA3 or RFX7 were elucidated. PCA3 up-regulated ABCA1 expression by binding to miR-140-5p to up-regulate RFX7 and ABCA1 expression in macrophages. PCA3 promoted RCT and impeded the progression of atherosclerosis by sponging miR-140-5p in apoE mice. Meanwhile, miR-140-5p also inhibit ABCA1 expression via downregulation of RFX7 to impede RCT and aggravate atherosclerosis. CONCLUSIONS: lncRNA PCA3 promotes ABCA1-mediated cholesterol efflux to inhibit atherosclerosis through sponging miR-140-5p and up-regulating RFX7.
目的：本研究旨在探讨长链非编码 RNA（lncRNA）前列腺癌抗原 3（PCA3）在动脉粥样硬化中的作用及其潜在机制。
方法：利用基因表达综合数据库（GEO）数据集对差异表达的 lncRNA、微小 RNA（miRNA）和信使 RNA（mRNA）进行分类。采用 qPCR 或 Western blot 法检测氧化型低密度脂蛋白（ox-LDL）处理的巨噬细胞中 PCA3、miR-140-5p、RFX7 和 ABCA1 的表达。采用油红 O 染色和高效液相色谱法评估巨噬细胞脂质蓄积。通过双荧光素酶报告基因检测或染色质免疫沉淀检测验证 PCA3、miR-140-5p、RFX7 和 ABCA1 启动子区之间的靶标关系。通过体内载脂蛋白 E（apoE）小鼠模型评估 PCA3 对胆固醇逆转运（RCT）和动脉粥样硬化的影响。
结果：泡沫细胞中 PCA3 表达下调，而 miR-140-5p 高表达。过表达 PCA3 促进 ABCA1 介导的胆固醇流出，减少巨噬细胞内脂质蓄积。此外，RFX7 与 ABCA1 启动子结合，增加 ABCA1 表达。阐明了 miR-140-5p 与 PCA3 或 RFX7 表达之间的靶向关系和相互作用。PCA3 通过与 miR-140-5p 结合，上调 RFX7 和 ABCA1 在巨噬细胞中的表达，从而上调 ABCA1 表达。在 apoE 小鼠中，PCA3 通过海绵吸附 miR-140-5p 促进 RCT，抑制动脉粥样硬化的进展。同时，miR-140-5p 通过下调 RFX7 抑制 ABCA1 表达，从而阻碍 RCT，加重动脉粥样硬化。
结论：lncRNA PCA3 通过海绵吸附 miR-140-5p 并上调 RFX7 促进 ABCA1 介导的胆固醇流出，从而抑制动脉粥样硬化。
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