Long Non-coding RNA ECRAR Triggers Post-natal Myocardial Regeneration by Activating ERK1/2 Signaling
Long Non-coding RNA ECRAR Triggers Post-natal Myocardial Regeneration by Activating ERK1/2 Signaling
复制标题
长非编码 RNA ECRAR 通过激活 ERK1/2 信号触发产后心肌再生
DOI：
10.1016/j.ymthe.2018.10.021
复制
发表时间：
2019-01-02
影响因子：
12.4
通讯作者：
Bin, Jianping
中科院分区：
文献类型：
--
作者：
Chen, Yanmei;Li, Xinzhong;Bin, Jianping
重新激活出生后心肌再生潜能可能是一种可行的策略来再生受伤的成人心脏。长链非编码rna （lncRNAs）参与调节细胞分化，但它们是否能在出生后心脏中引发再生反应仍然未知。在本研究中，通过表征胎儿到成人转变过程中人类心脏中的lncRNA转录组，我们发现3092个lncRNA存在差异表达，我们进一步鉴定了一种新的上调的胎儿lncRNA，我们称之为内源性心脏再生相关调节剂（endogenous cardiac regeneration-associated regulator， ECRAR），它在出生后第7天和成年大鼠心肌细胞（CMs）中促进DNA合成、有丝分裂和细胞分裂。过表达ECRAR可显著刺激心肌再生，诱导心肌梗死后心功能恢复。下调ECRAR抑制出生后1天CM增殖，阻止心肌梗死后恢复。E2F转录因子1 （E2F1）上调了ECRAR的转录水平。此外，ECRAR直接结合并促进细胞外信号调节激酶1和2 （ERK1/2）的磷酸化，导致cyclin D1和cyclin E1激活的下游靶点，进而激活E2F1。E2F1-ECRAR-ERK1/2信号形成一个正反馈回路，驱动细胞周期进程，从而促进CM增殖。这些发现表明我们新发现的ECRAR可能是心力衰竭的一个有价值的治疗靶点。
Reactivating post-natal myocardial regeneration potential may be a feasible strategy to regenerate the injured adult heart. Long non-coding RNAs (lncRNAs) have been implicated in regulating cellular differentiation, but whether they can elicit a regenerative response in the post-natal heart remains unknown. In this study, by characterizing the lncRNA transcriptome in human hearts during the fetal-to-adult transition, we found that 3,092 lncRNAs were differentially expressed, and we further identified a novel upregulated fetal lncRNA that we called endogenous cardiac regeneration-associated regulator (ECRAR), which promoted DNA synthesis, mitosis, and cytokinesis in post-natal day 7 and adult rat cardiomyocytes (CMs). Overexpression of ECRAR markedly stimulated myocardial regeneration and induced recovery of cardiac function after myocardial infarction (MI). Knockdown of ECRAR inhibited post-natal day 1 CM proliferation and prevented post-MI recovery. ECRAR was transcriptionally upregulated by E2F transcription factor 1 (E2F1). In addition, ECRAR directly bound to and promoted the phosphorylation of extracellular signal-regulated kinases 1 and 2 (ERK1/2), resulting in downstream targets of cyclin D1 and cyclin E1 activation, which, in turn, activated E2F1. The E2F1-ECRAR-ERK1/2 signaling formed a positive feedback loop to drive cell cycle progression, and, therefore, it promoted CM proliferation. These findings indicated that our newly discovered ECRAR may be a valuable therapeutic target for heart failure.