Long Noncoding RNA MALAT1 Regulates Endothelial Cell Function and Vessel Growth
Long Noncoding RNA MALAT1 Regulates Endothelial Cell Function and Vessel Growth
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DOI：
10.1161/circresaha.114.303265
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发表时间：
2014-04-25
影响因子：
20.1
通讯作者：
Dimmeler, Stefanie
中科院分区：
文献类型：
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作者：
Michalik, Katharina M.;You, Xintian;Dimmeler, Stefanie
原理：人类基因组包含大量编码RNA的序列，这些RNA没有被翻译，但通过不同的机制控制细胞功能。目的：我们研究了长非编码RNA在人内皮细胞中的表达，并阐明了高表达的转移相关肺腺癌转录本1(MALAT1)的功能。方法和结果：不同来源的内皮细胞表达相对高水平的保守的长非编码RNA MALAT1、牛磺酸上调表达基因1(TUG1)、母体表达3(MEG3)、linc00657和linc00493。低氧显著增加MALAT1，并控制内皮细胞的表型转换。通过小干扰RNAs或GapmeRs沉默MALAT1可诱导迁移反应，增加基本萌发和迁移，而内皮细胞的增殖受到抑制。当血管内皮生长因子进一步刺激血管生成时，MALAT1小干扰RNA诱导不连续的萌发，表明茎细胞有缺陷的增殖。体内研究证实，MALAT1的基因消融抑制了内皮细胞的增殖，减少了新生视网膜的血管形成。GapmeRs对MALAT1的药理抑制作用降低了后肢缺血后的血流恢复和毛细血管密度。基因表达谱分析和确证定量逆转录聚合酶链式反应表明，沉默MALAT1会损害多种细胞周期调节因子的表达。结论：沉默MALAT1在体外改变了内皮细胞增殖和迁移表型的平衡，其基因缺失或药物抑制抑制了体内血管的生长。
Rationale: The human genome harbors a large number of sequences encoding for RNAs that are not translated but control cellular functions by distinct mechanisms. The expression and function of the longer transcripts namely the long noncoding RNAs in the vasculature are largely unknown.Objective: Here, we characterized the expression of long noncoding RNAs in human endothelial cells and elucidated the function of the highly expressed metastasis-associated lung adenocarcinoma transcript 1 (MALAT1).Methods and Results: Endothelial cells of different origin express relative high levels of the conserved long noncoding RNAs MALAT1, taurine upregulated gene 1 (TUG1), maternally expressed 3 (MEG3), linc00657, and linc00493. MALAT1 was significantly increased by hypoxia and controls a phenotypic switch in endothelial cells. Silencing of MALAT1 by small interfering RNAs or GapmeRs induced a promigratory response and increased basal sprouting and migration, whereas proliferation of endothelial cells was inhibited. When angiogenesis was further stimulated by vascular endothelial growth factor, MALAT1 small interfering RNAs induced discontinuous sprouts indicative of defective proliferation of stalk cells. In vivo studies confirmed that genetic ablation of MALAT1 inhibited proliferation of endothelial cells and reduced neonatal retina vascularization. Pharmacological inhibition of MALAT1 by GapmeRs reduced blood flow recovery and capillary density after hindlimb ischemia. Gene expression profiling followed by confirmatory quantitative reverse transcriptase-polymerase chain reaction demonstrated that silencing of MALAT1 impaired the expression of various cell cycle regulators.Conclusions: Silencing of MALAT1 tips the balance from a proliferative to a migratory endothelial cell phenotype in vitro, and its genetic deletion or pharmacological inhibition reduces vascular growth in vivo.