Long Noncoding RNA-Enriched Vesicles Secreted by Hypoxic Cardiomyocytes Drive Cardiac Fibrosis
Long Noncoding RNA-Enriched Vesicles Secreted by Hypoxic Cardiomyocytes Drive Cardiac Fibrosis
复制标题
DOI：
10.1016/j.omtn.2019.09.003
复制
发表时间：
2019-12-06
影响因子：
8.8
通讯作者：
Thum, Thomas
中科院分区：
文献类型：
--
作者：
Kenneweg, Franziska;Bang, Claudia;Thum, Thomas
长链非编码RNA（lncRNAs）在心血管疾病中具有作为新型治疗靶点的潜力，但关于心脏中细胞间lncRNA转运机制的详细信息尚缺乏。在此，我们报道了在心肌缺血的情况下，由富含lncRNA的细胞外囊泡（EVs）的转移所介导的心肌细胞和成纤维细胞之间一种重要的新型相互作用。lncRNA分析鉴定出两种对缺氧敏感的lncRNAs：ENSMUST00000122745主要存在于小的细胞外囊泡中，而lncRNA Neat1在体外和体内都富集于大的细胞外囊泡中。囊泡被成纤维细胞摄取，触发促纤维化基因的表达。此外，在基础条件下，lncRNA Neat1受P53转录调控，在缺氧时受HIF2A转录调控。Neat1的功能在体外和体内得到了进一步阐明。体外沉默Neat1表明，Neat1对成纤维细胞和心肌细胞的存活是必不可少的，并影响成纤维细胞的功能（迁移能力降低、细胞周期停滞以及纤维化基因表达减少）。具有转化重要性的是，体内Neat1的基因缺失导致心肌梗死后心脏功能受损，突出了其转化相关性。
Long non-coding RNAs (lncRNAs) have potential as novel therapeutic targets in cardiovascular diseases, but detailed information about the intercellular lncRNA shuttling mechanisms in the heart is lacking. Here, we report an important novel crosstalk between cardiomyocytes and fibroblasts mediated by the transfer of lncRNA-enriched extracellular vesicles (EVs) in the context of cardiac ischemia. lncRNA profiling identified two hypoxia-sensitive lncRNAs: ENSMUST00000122745 was predominantly found in small EVs, whereas lncRNA Neat1 was enriched in large EVs in vitro and in vivo. Vesicles were taken up by fibroblasts, triggering expression of profibrotic genes. In addition, lncRNA Neat1 was transcriptionally regulated by P53 under basal conditions and by HIF2A during hypoxia. The function of Neat1 was further elucidated in vitro and in vivo. Silencing of Neat1 in vitro revealed that Neat1 was indispensable for fibroblast and cardiomyocyte survival and affected fibroblast functions (reduced migration capacity, stalled cell cycle, and decreased expression of fibrotic genes). Of translational importance, genetic loss of Neat1 in vivo resulted in an impaired heart function after myocardial infarction highlighting its translational relevance.