Inhibition of MicroRNA-92a Prevents Endothelial Dysfunction and Atherosclerosis in Mice
Inhibition of MicroRNA-92a Prevents Endothelial Dysfunction and Atherosclerosis in Mice
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DOI：
10.1161/circresaha.114.302213
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发表时间：
2014-01-31
影响因子：
20.1
通讯作者：
Tedgui, Alain
中科院分区：
文献类型：
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作者：
Loyer, Xavier;Potteaux, Stephane;Tedgui, Alain
研究原理：MicroRNAs（miRNAs）是一类在转录后水平调控蛋白质表达的非编码小分子RNA。我们假设一个特定的内皮miRNAs库可以被血流条件和炎症信号选择性地调节，并因此参与动脉粥样硬化的发展。目的：鉴定被剪切应力和氧化低密度脂蛋白（oxLDL）选择性调节的miRNAs，称为atheromiRs，并确定它们在动脉粥样硬化形成中的作用。方法和结果：HUVECs中的大规模miRNA分析将miR-92 a鉴定为动脉粥样硬化miR候选者，其表达优先被低剪切应力（SS）和致动脉粥样硬化oxLDL的组合上调。对小鼠动脉和人动脉粥样硬化斑块的atheroprone和动脉粥样硬化保护区的离体分析表明，miR-92 a在atheroprone低SS区域中优先表达。在Ldlr（-/-）小鼠中，高胆固醇血症显著增强了miR-92 a的表达，特别是在主动脉的动脉粥样硬化区。在靶向miR-92 a表达的功能获得和丧失实验中对内皮炎症的评估显示，miR-92 a调节oxLDL对内皮细胞的激活，更具体地说，在低SS条件下，这与Kruppel样因子2（KLF 2）、Kruppel样因子4（KLF 4）和细胞因子信号传导抑制因子5的调节相关。miR-92 a的表达受信号转导子和转录激活子3的调控，且具有SS和oxLDL依赖性。此外，在Ldlr（-/-）小鼠体内特异性阻断miR-92 a表达可减少内皮炎症，改变动脉粥样硬化的发展，减少斑块大小，促进更稳定的病变phenotype.Conclusions：oxLDL在atheroprone区域上调miR-92 a可促进内皮激活和动脉粥样硬化病变的发展。因此，miR-92 a抑制剂阿托莫西汀可能成为一种新的动脉粥样硬化保护治疗策略。
Rationale for Study: MicroRNAs (miRNAs) are small noncoding RNAs that regulate protein expression at post-transcriptional level. We hypothesized that a specific pool of endothelial miRNAs could be selectively regulated by flow conditions and inflammatory signals, and as such be involved in the development of atherosclerosis.Objective: To identify miRNAs, called atheromiRs, which are selectively regulated by shear stress and oxidized low-density lipoproteins (oxLDL), and to determine their role in atherogenesis.Methods and Results: Large-scale miRNA profiling in HUVECs identified miR-92a as an atheromiR candidate, whose expression is preferentially upregulated by the combination of low shear stress (SS) and atherogenic oxLDL. Ex vivo analysis of atheroprone and atheroprotected areas of mouse arteries and human atherosclerotic plaques demonstrated the preferential expression of miR-92a in atheroprone low SS regions. In Ldlr(-/-) mice, miR-92a expression was markedly enhanced by hypercholesterolemia, in particular in atheroprone areas of the aorta. Assessment of endothelial inflammation in gain- and loss-of-function experiments targeting miR-92a expression revealed that miR-92a regulated endothelial cell activation by oxLDL, more specifically under low SS conditions, which was associated with modulation of Kruppel-like factor 2 (KLF2), Kruppel-like factor 4 (KLF4), and suppressor of cytokine signaling 5. miR-92a expression was regulated by signal transducer and activator of transcription 3 in SS- and oxLDL-dependent manner. Furthermore, specific in vivo blockade of miR-92a expression in Ldlr(-/-) mice reduced endothelial inflammation and altered the development of atherosclerosis, decreasing plaque size and promoting a more stable lesion phenotype.Conclusions: Upregulation of miR-92a by oxLDL in atheroprone areas promotes endothelial activation and the development of atherosclerotic lesions. Therefore, miR-92a antagomir seems as a new atheroprotective therapeutic strategy.