The role of the LncRNA-FA2H-2-MLKL pathway in atherosclerosis by regulation of autophagy flux and inflammation through mTOR-dependent signaling
The role of the LncRNA-FA2H-2-MLKL pathway in atherosclerosis by regulation of autophagy flux and inflammation through mTOR-dependent signaling
复制标题
LncRNA-FA2H-2-MLKL通路在动脉粥样硬化中的作用
DOI：
10.1038/s41418-018-0235-z
复制
发表时间：
2019-09-01
影响因子：
12.4
通讯作者：
Wang, Qian
中科院分区：
文献类型：
--
作者：
Guo, Feng-Xia;Wu, Qian;Wang, Qian
动脉粥样硬化是动脉壁的一种进行性慢性炎症。长链非编码RNA（lncRNA）参与炎症反应，但其在动脉粥样硬化中的确切作用机制尚不清楚。我们的微阵列分析显示，lncRNA-FA 2 H-2的水平显着降低氧化低密度脂蛋白（OX-LDL）。生物信息学分析表明，混合谱系激酶结构域样蛋白（MLKL）可能受lncRNA-FA 2 H-2的调控。体外实验表明，lncRNA-FA 2 H-2与MLKL基因启动子相互作用，下调MLKL的表达，其-750 ~471之间的结合位点是lncRNA-FA 2 H-2对MLKL的反应性所必需的。沉默lncRNA-FA 2 H-2和过表达MLKL可激活炎症并抑制自噬通量。lncRNA-FA 2 H-2的敲低和MLKL的过表达均能显著加重OX-LDL诱导的炎症反应。我们发现3-甲基腺嘌呤（3-MA）和Atg 7-shRNA增强了由lncRNA-FA 2 H-2敲低和MLKL过表达诱导的炎症反应。我们证明MLKL对自噬的影响可能与雷帕霉素（mTOR）依赖性信号通路的机制靶点有关。用apoE基因敲除小鼠喂养西方饮食的体内实验表明，LncRNA-FA 2 H-2敲低降低了微管相关蛋白1轻链3 II和溶酶体相关膜蛋白1的微管相关表达，但增加了动脉粥样硬化病变中的多价螯合体1（p62）、MLKL、血管细胞粘附分子-1、单核细胞趋化蛋白-1和白细胞介素-6的表达。我们的研究结果表明，lncRNA-FA 2 H-2-MLKL通路是必不可少的自噬和炎症的调节，并建议lncRNA-FA 2 H-2和MLKL可以作为潜在的治疗靶点，以改善动脉粥样硬化相关疾病。
Atherosclerosis is a progressive, chronic inflammation in arterial walls. Long noncoding RNAs (lncRNAs) participate in inflammation, but the exact mechanism in atherosclerosis is unclear. Our microarray analyses revealed that the levels of lncRNA-FA2H-2 were significantly decreased by oxidized low-density lipoprotein (OX-LDL). Bioinformatics analyses indicated that mixed lineage kinase domain-like protein (MLKL) might be regulated by lncRNA-FA2H-2. In vitro experiments showed that lncRNA-FA2H-2 interacted with the promoter of the MLKL gene, downregulated MLKL expression, and the binding sites between -750 and 471 were necessary for lncRNA-FA2H-2 responsiveness to MLKL. Silencing lncRNA-FA2H-2 and overexpression of MLKL could activate inflammation and inhibited autophagy flux. Both lncRNA-FA2H-2 knockdown and overexpression of MLKL could significantly aggravate inflammatory responses induced by OX-LDL. We found that the 3-methyladenine (3-MA) and Atg7-shRNA enhanced inflammatory responses induced by knockdown of lncRNA-FA2H-2 and overexpression of MLKL. We demonstrated that the effects of MLKL on autophagy might be associated with a mechanistic target of rapamycin (mTOR)-dependent signaling pathways. In vivo experiments with apoE knockout mice fed a western diet demonstrated that LncRNA-FA2H-2 knockdown decreased microtubule-associated expression of microtubule-associated protein 1 light chain 3 II and lysosome-associated membrane protein 1, but increased expression of sequestosome 1 (p62), MLKL, vascular cell adhesion molecule-1, monocyte chemoattractant protein-1, and interleukin-6 in atherosclerotic lesions. Our findings indicated that the lncRNA-FA2H-2-MLKL pathway is essential for regulation of autophagy and inflammation, and suggested that lncRNA-FA2H-2 and MLKL could act as potential therapeutic targets to ameliorate atherosclerosis-related diseases.