Liang Xue, Xu Zhao, Yuan Meng, Zhang Yue, Zhao Bo, Wang Junqian, Zhang Aixue, Li Guangping
Tianjin Key Laboratory of Ionic-Molecular Function of Cardiovascular Disease, Department of Cardiology, Tianjin Institute of Cardiology, Second Hospital of Tianjin Medical University, Tianjin 300211, P.R. China.
Int J Mol Med. 2016 Apr;37(4):967-75. doi: 10.3892/ijmm.2016.2497. Epub 2016 Feb 22.
Programmed cell death 4 (PDCD4) is involved in a number of bioprocesses, such as apoptosis and inflammation. However, its regulatory mechanisms in atherosclerosis remain unclear. In this study, we investigated the role and mechanisms of action of PDCD4 in high-fat diet-induced atherosclerosis in mice and in foam cells (characteristic pathological cells in atherosclerotic lesions) derived from ox-LDL-stimulated macrophages. MicroRNA (miR)-16 was predicted to bind PDCD4 by bioinformatics analysis. In the mice with atherosclerosis and in the foam cells, PDCD4 protein expression (but not the mRNA expression) was enhanced, while that of miR‑16 was reduced. Transfection with miR‑16 mimic decreased the activity of a luciferase reporter containing the 3' untranslated region (3'UTR) of PDCD4 in the macrophage-derived foam cells. Conversely, treatment with miR‑16 inhibitor enhanced the luciferase activity. However, by introducing mutations in the predicted binding site located in the 3'UTR of PDCD4, the miR‑16 mimic and inhibitor were unable to alter the level of PDCD4, suggesting that miR‑16 is a direct negative regulator of PDCD4 in atherosclerosis. Furthermore, transfection wtih miR‑16 mimic and siRNA targeting PDCD4 suppressed the secretion and mRNA expression of pro-inflammatory factors, such as interleukin (IL)-6 and tumor necrosis factor-α (TNF‑α), whereas it enhanced the secretion and mRNA expression of the anti-inflammatory factor, IL-10. Treatment with miR‑16 inhibitor exerted the opposite effects. In addition, the phosphorylation of p38 and extracellular signal-regulated kinase (ERK), and nuclear factor-κB (NF-κB) expression were altered by miR‑16. In conclusion, our data demonstrate that the targeting of PDCD4 by miR‑16 may suppress the activation of inflammatory macrophages though mitogen-activated protein kinase (MAPK) and NF-κB signaling in atherosclerosis; thus, PDCD4 may prove to be a potential therapeutic target in the treatment of atherosclerosis.
程序性细胞死亡4（PDCD4）参与多种生物过程，如细胞凋亡和炎症。然而，其在动脉粥样硬化中的调控机制仍不清楚。在本研究中，我们调查了PDCD4在高脂饮食诱导的小鼠动脉粥样硬化以及氧化低密度脂蛋白（ox-LDL）刺激的巨噬细胞来源的泡沫细胞（动脉粥样硬化病变中的特征性病理细胞）中的作用及作用机制。通过生物信息学分析预测微小RNA（miR）-16可与PDCD4结合。在动脉粥样硬化小鼠和泡沫细胞中，PDCD4蛋白表达（而非mRNA表达）增强，而miR-16表达降低。在巨噬细胞来源的泡沫细胞中，转染miR-16模拟物可降低含有PDCD4 3'非翻译区（3'UTR）的荧光素酶报告基因的活性。相反，用miR-16抑制剂处理可增强荧光素酶活性。然而，通过在PDCD4 3'UTR中的预测结合位点引入突变，miR-16模拟物和抑制剂无法改变PDCD4水平，这表明miR-16是动脉粥样硬化中PDCD4的直接负调节因子。此外，转染miR-16模拟物和靶向PDCD4的小干扰RNA（siRNA）可抑制促炎因子如白细胞介素（IL）-6和肿瘤坏死因子-α（TNF-α）的分泌及mRNA表达，而增强抗炎因子IL-10的分泌及mRNA表达。用miR-16抑制剂处理则产生相反的效果。此外，miR-16可改变p38和细胞外信号调节激酶（ERK）的磷酸化以及核因子-κB（NF-κB）的表达。总之，我们的数据表明，在动脉粥样硬化中，miR-16靶向PDCD4可能通过丝裂原活化蛋白激酶（MAPK）和NF-κB信号通路抑制炎性巨噬细胞的活化；因此，PDCD4可能是治疗动脉粥样硬化的潜在治疗靶点。
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