SIRT6-mediated transcriptional suppression of MALAT1 is a key mechanism for endothelial to mesenchymal transition
SIRT6-mediated transcriptional suppression of MALAT1 is a key mechanism for endothelial to mesenchymal transition
复制标题
SIRT6 介导的 MALAT1 转录抑制是内皮细胞向间质细胞转化的关键机制
DOI：
10.1016/j.ijcard.2019.07.082
复制
发表时间：
2019
影响因子：
3.5
通讯作者：
Yong Zhang
中科院分区：
文献类型：
--
作者：
Wei Qin;Longyin Zhang;Zhange Li;Dan Xiao;Yue Zhang;Huan Yang;Xin Liu;Haiying Zhang;Xiaohui Chen;Chaoqian Xu;Baofeng Yang;Yong Zhang
背景血管老化对心血管疾病有着深远的影响。内皮细胞向间充质细胞转化（EndMT）是指内皮细胞获得间充质细胞特性的过程，在内皮细胞衰老模型中发现了这种过程。然而，EndMT是否发生在体内老化过程中，EndMT对血管生物学的功能意义和潜在的机制仍然unknow.Methods和resultsIn这项研究中，我们检查了血管内皮细胞从年轻（2个月大）和老年（18个月大）小鼠，并证明，老年内皮细胞进行EndMT。此外，transwell实验显示EndMT过程伴随着内皮通透性的增加。结果发现，sirtuin 6（SIRT 6），烟酰胺腺嘌呤二核苷酸+（NAD+）依赖性组蛋白去乙酰化酶，在内皮细胞老化过程中下调。在年轻的EC中敲低SIRT 6可以诱导EndMT。接下来，我们鉴定了5种在EC中富集SIRT 6下游效应子的长非编码RNA;只有转移相关肺腺癌转录本1（MALAT 1）在老年EC中显著上调。SIRT 6的敲除可以增加MALAT 1水平。此外，ChIP检测和荧光素酶报告基因检测证实SIRT 6直接结合到MALAT 1的启动子区并抑制MALAT 1的表达。最后，我们证明了MALAT 1介导的衰老诱导的EndMT通过增加Snail expression.ConclusionOur study providesin vivo evidence表明，内皮细胞在血管衰老过程中经历EndMT，这增加了内皮细胞的通透性。SIRT 6介导的MALAT 1转录抑制是EndMT的关键机制。EndMT的调控可能成为延缓衰老相关血管疾病的一种新的治疗策略。
BackgroundVascular aging has profound effects on cardiovascular diseases. Endothelial to mesenchymal transition (EndMT) is defined as the acquisition of mesenchymal characteristics by endothelial cells (ECs) and has been found induced in a model of ECs aging. However, whether EndMT occurs during agingin vivo, the functional significance of EndMT on vascular biology and the underlying mechanisms remain unknown.Methods and resultsIn this study, we examined the vascular ECs from young (2 months old) and old (18 months old) mice, and demonstrated that aged ECs underwent EndMT. Moreover, the transwell assay showed that EndMT process was accompanied by increased endothelial permeability. It was found that sirtuin 6 (SIRT6), a nicotinamide adenine dinucleotide+(NAD+)-dependent histone deacetylase, was down-regulated during ECs aging. Knockdown of SIRT6 in young ECs could induce EndMT. Next, we identified five long non-coding RNAs that are enriched in ECs for downstream effector of SIRT6; only metastasis associated lung adenocarcinoma transcript 1 (MALAT1) was significantly up-regulated in aged ECs. Knockdown of SIRT6 could increase MALAT1 levels. Furthermore, the ChIP assay and luciferase reporter gene assay confirmed that SIRT6 bound directly to the promoter region of MALAT1 and suppressed MALAT1 expression. Finally, we demonstrated that MALAT1 mediated aging-induced EndMT through increasing Snail expression.ConclusionOur study providesin vivoevidence that ECs undergo EndMT during vascular aging, which increases endothelial permeability. SIRT6-mediated transcriptional suppression of MALAT1 is a key mechanism for EndMT. Manipulating EndMT may be considered as a new therapeutic strategy for retarding aging-associated vascular diseases.