miR-199a-3p promotes cardiomyocyte proliferation by inhibiting Cd151 expression
miR-199a-3p promotes cardiomyocyte proliferation by inhibiting Cd151 expression
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miR-199a-3p 通过抑制 Cd151 表达促进心肌细胞增殖。
DOI：
10.1016/j.bbrc.2019.05.174
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发表时间：
2019-08-13
影响因子：
3.1
通讯作者：
Wei, Ke
中科院分区：
文献类型：
--
作者：
Tao, Ying;Zhang, Hongjie;Wei, Ke
成年哺乳动物心肌细胞的再生能力非常有限，据信有一种强大的内在机制阻止心肌细胞进入细胞周期。促进心肌细胞增殖的microRNA可以作为探针来鉴定抑制心肌细胞增殖的新基因，从而剖析防止心肌细胞复制的机制。特别是，已经发现miR-199 a-3 p是啮齿动物心肌细胞增殖的有效激活剂，尽管其分子靶点仍然难以捉摸。在这里，我们确定Cd 151作为miR-199 a-3 p的直接靶点，并且其表达被miR-199 a-3 p极大地抑制。Cd 151功能获得性降低心肌细胞增殖，相反Cd 151功能丧失性增加心肌细胞增殖。Cd 151的过表达阻断了miR-199 a-3 p对心肌细胞增殖的激活作用，表明Cd 151是miR-199 a-3 p在心肌细胞中的功能靶点。从机制上讲，我们发现Cd 151诱导p38表达，这是一种已知的心肌细胞增殖的负调节因子，并且p38的药理学抑制挽救了Cd 151对增殖的抑制作用。总之，这项工作提出Cd 151作为心肌细胞增殖的新抑制剂，这可能为开发促进心脏再生的疗法提供新的分子靶点。(C)2019爱思唯尔公司All rights reserved.
Adult mammalian cardiomyocytes have extremely limited capacity to regenerate, and it is believed that a strong intrinsic mechanism is prohibiting the cardiomyocytes from entering the cell cycle. microRNAs that promote proliferation in cardiomyocyte can be used as probes to identify novel genes suppressing cardiomyocytes proliferation, thus dissecting the mechanism(s) preventing cardiomyocytes from duplication. In particular, miR-199a-3p has been found as a potent activator of proliferation in rodent cardiomyocyte, although its molecular targets remain elusive. Here, we identified Cd151 as a direct target of miR-199a-3p, and its expression is greatly suppressed by miR-199a-3p. Cd151 gain-of-function reduced cardiomyocyte proliferation, conversely Cd151 loss-of-function increased cardiomyocytes proliferation. Overexpression of Cd151 blocks the activating effect of miR-199a-3p on cardiomyocyte proliferation, suggesting Cd151 is a functional target of miR-199a-3p in cardiomyocytes. Mechanistically, we found that Cd151 induces p38 expression, a known negative regulator of cardiomyocyte proliferation, and pharmacological inhibition of p38 rescued the inhibitory effect of Cd151 on proliferation. Together, this work proposes Cd151 as a novel suppressor of cardiomyocyte proliferation, which may provide a new molecular target for developing therapies to promote cardiac regeneration. (C) 2019 Elsevier Inc. All rights reserved.