Loss of long non-coding RNA CRRL promotes cardiomyocyte regeneration and improves cardiac repair by functioning as a competing endogenous RNA
Loss of long non-coding RNA CRRL promotes cardiomyocyte regeneration and improves cardiac repair by functioning as a competing endogenous RNA
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长链非编码 RNA CRRL 的缺失可作为竞争性内源性 RNA 促进心肌细胞再生并改善心脏修复
DOI：
10.1016/j.yjmcc.2018.08.013
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发表时间：
2018-09-01
影响因子：
5
通讯作者：
Bin, Jianping
中科院分区：
文献类型：
--
作者：
Chen, Guojun;Li, Hairui;Bin, Jianping
长链非编码RNA（lncRNA）在心肌肥大的发展中发挥着关键作用，并可能刺激内源性心肌再生以预防心肌梗死（MI）后的心力衰竭。然而，lncRNA是否参与调节MI后心肌再生仍不清楚。本研究旨在鉴定参与内源性心肌细胞（CM）再生的人源lncRNA。通过分析公开的人类胎儿和正常成人心脏组织的 RNA-seq 数据，我们发现了一种新型的人源性上调 lncRNA，称为心肌细胞再生相关 lncRNA (CRRL)。生物信息学分析表明CRRL参与CM增殖的负调控。首先，我们观察到 CRRL 的丧失会减弱成年大鼠的心肌梗死后重塑并保留心脏功能。通过功能丧失方法，我们发现 CRRL 敲低可促进新生大鼠 CM 体内和体外增殖。此外，我们证明CRRL通过直接结合miR-199a-3p作为竞争性内源RNA（ceRNA），从而增加Hopx的表达，Hopx是miR-199a-3p的靶基因和CM增殖的关键负调节因子。因此，CRRL通过直接结合miR-199a-3p来抑制心肌细胞再生，表明CRRL的缺失促进心肌再生，可能是心力衰竭的一种新的潜在治疗策略。
Long noncoding RNAs (lncRNAs) play critical roles in the development of myocardial hypertrophy and may stimulate endogenous myocardial regeneration to prevent heart failure after myocardial infarction (MI). However, whether lncRNAs are involved in regulating myocardial regeneration after MI remains unclear. The present study aimed to identify human-derived lncRNAs that are involved in endogenous cardiomyocyte (CM) regeneration. By analyzing publicly available RNA-seq data of human fetal and normal adult cardiac tissues, we identified a novel human-derived adult upregulated lncRNA designated cardiomyocyte regeneration-related lncRNA (CRRL). Bioinformatics analysis indicated that CRRL is involved in the negative regulation of CM proliferation. First, we observed that the loss of CRRL attenuates post-MI remodeling and preserves cardiac function in adult rats. Through loss-of-function approaches, we found that CRRL knockdown promotes neonatal rat CM proliferation both in vivo and in vitro. Furthermore, we demonstrated that CRRL acts as a competing endogenous RNA (ceRNA) by directly binding to miR-199a-3p and thereby increasing the expression of Hopx, a target gene of miR-199a-3p and a critical negative regulatory factor of CM proliferation. Thus, CRRL suppresses cardiomyocyte regeneration by directly binding to miR-199a-3p, indicating that loss of CRRL facilitates myocardial regeneration and may be a new potential therapeutic strategy for heart failure.