Department of Pharmacology (State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), Harbin Medical University, Harbin, Heilongjiang, China; School of Pharmacy, Jining Medical University, Rizhao, Shandong, China.
Department of Pharmacology (State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), Harbin Medical University, Harbin, Heilongjiang, China.
Int J Cardiol. 2019 Nov 15;295:7-13. doi: 10.1016/j.ijcard.2019.07.082. Epub 2019 Jul 30.
Vascular 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 aging in vivo, the functional significance of EndMT on vascular biology and the underlying mechanisms remain unknown.
In 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.
Our study provides in vivo evidence 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.
血管衰老对心血管疾病有深远影响。内皮细胞向间充质转化（EndMT）被定义为内皮细胞（ECs）获得间充质特征，并已在 ECs 衰老模型中发现诱导其发生。然而，在体内衰老过程中是否发生 EndMT，EndMT 对血管生物学的功能意义以及潜在机制尚不清楚。
在这项研究中，我们检测了来自年轻（2 个月大）和年老（18 个月大）小鼠的血管 ECs，并证明了衰老的 ECs 发生了 EndMT。此外，transwell 测定表明 EndMT 过程伴随着内皮通透性的增加。结果发现，烟酰胺腺嘌呤二核苷酸（NAD）依赖性组蛋白去乙酰化酶 Sirtuin 6（SIRT6）在 ECs 衰老过程中下调。在年轻的 ECs 中敲低 SIRT6 可以诱导 EndMT。接下来，我们鉴定了五个在 ECs 中富含的长非编码 RNA，它们是 SIRT6 的下游效应物；只有转移相关肺腺癌转录本 1（MALAT1）在衰老的 ECs 中显著上调。敲低 SIRT6 可以增加 MALAT1 水平。此外，ChIP 测定和荧光素酶报告基因测定证实 SIRT6 直接结合 MALAT1 的启动子区域并抑制 MALAT1 表达。最后，我们证明 MALAT1 通过增加 Snail 表达介导衰老诱导的 EndMT。
本研究提供了体内证据，表明 ECs 在血管衰老过程中发生 EndMT，从而增加内皮通透性。SIRT6 介导的 MALAT1 转录抑制是 EndMT 的关键机制。操纵 EndMT 可能被视为延缓与衰老相关的血管疾病的新治疗策略。
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