Attenuation of microRNA-16 derepresses the cyclins D1, D2 and E1 to provoke cardiomyocyte hypertrophy.
Attenuation of microRNA-16 derepresses the cyclins D1, D2 and E1 to provoke cardiomyocyte hypertrophy.
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microRNA-16 的减弱会解除细胞周期蛋白 D1、D2 和 E1 的抑制，从而引发心肌细胞肥大
DOI：
10.1111/jcmm.12445
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发表时间：
2015-03
影响因子：
5.3
通讯作者：
Shan ZX
中科院分区：
文献类型：
--
作者：
Huang S;Zou X;Zhu JN;Fu YH;Lin QX;Liang YY;Deng CY;Kuang SJ;Zhang MZ;Liao YL;Zheng XL;Yu XY;Shan ZX
细胞周期蛋白/视网膜母细胞瘤蛋白（pRb）通路参与心肌细胞肥大。microRNAs（miRNAs）是一类内源性小分子非编码RNA，在心肌肥厚中发挥重要作用。但是，心肌肥厚过程中cyclin/Rb通路是否受到miRNAs的调控尚不清楚。本研究探讨microRNA-16（miR-16）在心肌细胞肥大过程中对cyclin/Rb信号通路的调节作用。采用腹主动脉缩窄（AAC）大鼠、横主动脉缩窄（TAC）小鼠和苯肾上腺素（PE）皮下注射小鼠，分别建立肥大动物模型。此外，还分别建立了基于PE促进的乳鼠心室肌细胞和基于Ang-II诱导的乳鼠心室肌细胞肥大的细胞模型。我们证明了miR-16在大鼠和小鼠的肥大心肌和肥大心肌细胞中的表达显著降低。过表达miR-16可抑制大鼠心肌肥大和培养心肌细胞的肥大表型，抑制miR-16可诱导心肌细胞的肥大表型。肥大心肌和肥大心肌细胞中cyclin D1、D2和E1的表达以及磷酸化pRb的表达均增加，但可被miR-16的增强表达逆转。细胞周期蛋白D1，D2和E1，而不是pRb，被进一步验证为由miR-16转录后调节。此外，信号转导和转录激活因子-3和c-Myc在心肌肥大期间被激活，抑制它们可防止miR-16衰减。因此，下调miR-16的表达可通过下调cyclin D1、D2和E1的表达，激活cyclin/Rb信号通路，从而诱导心肌细胞肥大，提示miR-16可能是调控心肌肥大的靶点。
Cyclins/retinoblastoma protein (pRb) pathway participates in cardiomyocyte hypertrophy. MicroRNAs (miRNAs), the endogenous small non-coding RNAs, were recognized to play significant roles in cardiac hypertrophy. But, it remains unknown whether cyclin/Rb pathway is modulated by miRNAs during cardiac hypertrophy. This study investigates the potential role of microRNA-16 (miR-16) in modulating cyclin/Rb pathway during cardiomyocyte hypertrophy. An animal model of hypertrophy was established in a rat with abdominal aortic constriction (AAC), and in a mouse with transverse aortic constriction (TAC) and in a mouse with subcutaneous injection of phenylephrine (PE) respectively. In addition, a cell model of hypertrophy was also achieved based on PE-promoted neonatal rat ventricular cardiomyocyte and based on Ang-II-induced neonatal mouse ventricular cardiomyocyte respectively. We demonstrated that miR-16 expression was markedly decreased in hypertrophic myocardium and hypertrophic cardiomyocytes in rats and mice. Overexpression of miR-16 suppressed rat cardiac hypertrophy and hypertrophic phenotype of cultured cardiomyocytes, and inhibition of miR-16 induced a hypertrophic phenotype in cardiomyocytes. Expressions of cyclins D1, D2 and E1, and the phosphorylated pRb were increased in hypertrophic myocardium and hypertrophic cardiomyocytes, but could be reversed by enforced expression of miR-16. Cyclins D1, D2 and E1, not pRb, were further validated to be modulated post-transcriptionally by miR-16. In addition, the signal transducer and activator of transcription-3 and c-Myc were activated during myocardial hypertrophy, and inhibitions of them prevented miR-16 attenuation. Therefore, attenuation of miR-16 provoke cardiomyocyte hypertrophy via derepressing the cyclins D1, D2 and E1, and activating cyclin/Rb pathway, revealing that miR-16 might be a target to manage cardiac hypertrophy.
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影响因子：
37.8
作者：
Heymans, Stephane;Corsten, Maarten F.;Schroen, Blanche
通讯作者：
Schroen, Blanche
DOI：
10.1073/pnas.93.16.8750
发表时间：
1996-08-06
影响因子：
11.1
作者：
Hannan, RD;Stefanovsky, V;Rothblum, LI
通讯作者：
Rothblum, LI
MicroRNA 16 增强心脏微环境中人骨髓间充质干细胞向体外肌源表型的分化
影响因子：
6.1
作者：
Liu, Ju-Li;Jiang, Li;Shan, Zhi-Xin
通讯作者：
Shan, Zhi-Xin
miR-16 家族通过调节多个细胞周期基因诱导细胞周期停滞。
影响因子：
14.9
作者：
Liu Q;Fu H;Sun F;Zhang H;Tie Y;Zhu J;Xing R;Sun Z;Zheng X
通讯作者：
Zheng X
影响因子：
4
作者：
Li, Qing;Song, Xiao-Wei;Jing, Qing
通讯作者：
Jing, Qing