LncRNA HOTAIR functions as a competing endogenous RNA to upregulate SIRT1 by sponging miR-34a in diabetic cardiomyopathy
LncRNA HOTAIR functions as a competing endogenous RNA to upregulate SIRT1 by sponging miR-34a in diabetic cardiomyopathy
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在糖尿病心肌病中，LncRNA HOTAIR 作为竞争性内源性 RNA，通过海绵 miR-34a 上调 SIRT1。
DOI：
10.1002/jcp.27296
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发表时间：
2019-04-01
影响因子：
5.6
通讯作者：
Zhang, Yanzhou
中科院分区：
文献类型：
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作者：
Gao, Lu;Wang, Xiaofang;Zhang, Yanzhou
hox转录反义RNA （HOTAIR）长链非编码RNA （lncRNA）是一种丰富且保守的印迹基因，与许多重要的生物过程和疾病有关。然而，迄今为止，尚未研究HOTAIR在糖尿病性心肌病（DCM）中的意义。本研究旨在确定HOTAIR是否可以调控DCM，并阐明相关机制。在体内，通过腹腔注射链脲佐菌素诱导小鼠1型糖尿病。注射STZ 12周后，使用腺相关病毒系统实现心肌细胞特异性HOTAIR过表达。体外利用H9c2探讨HOTAIR调节高糖诱导心肌细胞损伤的潜在分子机制。通过荧光素酶报告基因测定和RNA免疫沉淀（RIP）来探索HOTAIR、microRNA-34a （miR-34a）和Sirtuin 1 （SIRT1）之间的关系。HOTAIR在糖尿病小鼠心脏中的表达明显降低。在高糖诱导的H9c2中，HOTAIR的下调导致体外氧化损伤、炎症和细胞凋亡增加。在STZ处理的小鼠中，心肌细胞特异性过表达HOTAIR可改善心功能，降低氧化应激和炎症，并减轻心肌细胞死亡。机制上，与STZ处理的对照心脏相比，过表达hotair的心脏中SIRT1/forkhead box蛋白O1的表达显著增加。此外，我们发现HOTAIR在H9c2中充当miR-34a的分子海绵，SIRT1被确定为miR-34a的靶标。此外，HOTAIR对SIRT1缺乏小鼠DCM的保护作用在体内被消除。HOTAIR通过海绵miR-34a激活SIRT1表达来保护DCM。
TheHOX transcript antisense RNA (HOTAIR) long noncoding RNA (lncRNA), a highly abundant and conserved imprinted gene, has been implicated in many essential biological processes and diseases. However, to date, the significance of HOTAIR in diabetic cardiomyopathy (DCM) has never been investigated. The current study was designed to determine whether DCM can be regulated by HOTAIR and to elucidate the related mechanism. In vivo, streptozotocin (STZ) was injected intraperitoneally to induce type 1 diabetes in mice. Cardiomyocyte specific HOTAIR overexpression was achieved using an adeno-associated virus system 12 weeks after STZ injection. In vitro, H9c2 were used to explore the potential molecular mechanism of HOTAIR in the regulation of high-glucose-induced cardiomyocyte injury. Luciferase reporter assay and RNA immunoprecipitation (RIP) were performed to explore the relationship between HOTAIR, microRNA-34a (miR-34a), and Sirtuin 1 (SIRT1). HOTAIR expression was significantly decreased in diabetic mice hearts. Knockdown of HOTAIR in high glucose-induced H9c2 resulted in increased oxidative injury, inflammation, and apoptosis in vitro. Cardiomyocyte-specific overexpression of HOTAIR improved cardiac function, decreased oxidative stress and inflammation, and attenuated myocyte death in mice treated with STZ. Mechanistically, the expression of SIRT1/forkhead box protein O1 was significantly increased in the HOTAIR-overexpressing hearts compared with the control hearts treated with STZ. Moreover, we found HOTAIR functioned as a molecular sponge of miR-34a in H9c2 and SIRT1 was identified as a target of miR-34a. Furthermore, the protective effects of HOTAIR on DCM was abolished in SIRT1 deficiency mice in vivo. HOTAIR protected against DCM via activation of the SIRT1 expression by sponging miR-34a.