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长链非编码RNA Tincr在心肌细胞肥大中以依赖于miR-31-5p的方式调节蛋白激酶Cε的表达。

LncRNA Tincr regulates PKCɛ expression in a miR-31-5p-dependent manner in cardiomyocyte hypertrophy.

作者信息

Li Hao, Shi Hongtao, Zhang Fan, Xue Honghong, Wang Lei, Tian Jing, Xu Jianrong, Han Qinghua

机构信息

The First Clinical Medical School, Shanxi Medical University, No. 56 Xinjian South Road, Taiyuan, 030001, Shanxi, People's Republic of China.

Department of Cardiology, The First Hospital of Shanxi Medical University, Taiyuan, 030001, Shanxi, People's Republic of China.

出版信息

Naunyn Schmiedebergs Arch Pharmacol. 2020 Dec;393(12):2495-2506. doi: 10.1007/s00210-020-01847-9. Epub 2020 Mar 10.

Abstract

Cardiomyocyte hypertrophy is a fatal factor in heart disease resulting in heart failure and even mortality. Although many studies have been focusing on the pathogenesis of cardiomyocyte hypertrophy, the exact molecular mechanisms are still unexclusive. In this study, we first found that the expression level of lncRNA Tincr was significantly decreased in the myocardial tissues of TAC mouse models of cardiomyocyte hypertrophy, and this result was further confirmed in H9C2 cells, a widely used rat myoblast cell lines. More intriguingly, we demonstrated that the aberration of Tincr is essential to the pathogenesis of cardiomyocyte hypertrophy, indicated by the re-induction of Tincr improving the heart functions of hypertrophic mice. In mechanism, we identified miR-31-5p as a direct target of Tincr using a widely used online bioinformatics tool StarBase, and this result was further experimentally validated using dual-luciferase reporter assay and real-time PCR. Also, we identified PRKCE as a direct target of miR-31-5p, and loss function of miR-31-5p significantly blocks the positive regulatory effect of Tincr on PRKCE expression in H9C2 cells. The knockdown of Tincr resulted in increased cardiomyocyte size, and, however, inhibition of miR-31-5p or overexpression of PRKCE significantly reversed the increased cardiomyocyte size. Taken together, our study showed that a novel Tincr-miR-31-5p axis targeting PRKCE was involved in cardiomyocyte hypertrophy, indicating that it may provide potential therapy in cardiomyocyte hypertrophy.

摘要

心肌细胞肥大是导致心力衰竭甚至死亡的心脏病中的一个致命因素。尽管许多研究一直聚焦于心肌细胞肥大的发病机制,但其确切的分子机制仍不明确。在本研究中,我们首先发现lncRNA Tincr的表达水平在心肌细胞肥大的TAC小鼠模型的心肌组织中显著降低,并且这一结果在广泛使用的大鼠成肌细胞系H9C2细胞中得到进一步证实。更有趣的是,我们证明Tincr的异常对于心肌细胞肥大的发病机制至关重要,Tincr的重新诱导改善肥厚小鼠的心脏功能就表明了这一点。在机制方面,我们使用广泛使用的在线生物信息学工具StarBase将miR-31-5p鉴定为Tincr的直接靶点,并且这一结果通过双荧光素酶报告基因检测和实时PCR进一步在实验上得到验证。此外,我们将PRKCE鉴定为miR-31-5p的直接靶点,并且miR-31-5p的功能缺失显著阻断了Tincr对H9C2细胞中PRKCE表达的正向调节作用。Tincr的敲低导致心肌细胞大小增加,然而,miR-31-5p的抑制或PRKCE的过表达显著逆转了心肌细胞大小的增加。综上所述,我们的研究表明一个靶向PRKCE的新型Tincr-miR-31-5p轴参与了心肌细胞肥大,表明它可能为心肌细胞肥大提供潜在的治疗方法。

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