The microRNA-204-5p inhibits APJ signalling and confers resistance to cardiac hypertrophy and dysfunction.
The microRNA-204-5p inhibits APJ signalling and confers resistance to cardiac hypertrophy and dysfunction.
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DOI：
10.1002/ctm2.693
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发表时间：
2022-01
影响因子：
10.6
通讯作者：
Vikram A
中科院分区：
文献类型：
--
作者：
Gaddam RR;Kim YR;Jacobs JS;Yoon JY;Li Q;Cai A;Shankaiahgari H;London B;Irani K;Vikram A
MicroRNA调节心脏肥大的发展，这先于并预测心力衰竭的风险。microRNA-204 - 5 p（miR-204）在心肌细胞中表达良好，但其在心脏肥大和心功能不全（CH/CD）中的作用仍知之甚少。研究方法：我们对经主动脉缩窄术（TAC）后5周缺乏或过表达miR-204的小鼠心脏进行了RNA测序、超声心动图和分子/形态学分析。使用新生大鼠心肌细胞、H9 C2和HEK 293细胞来确定miR-204的机制作用。牵张诱导miR-204表达，并且miR-204抑制牵张诱导的H9 C2细胞肥大反应。缺乏miR-204的小鼠在压力超负荷期间表现出对CH/CD的更高易感性，这被腺相关病毒血清型9介导的心脏选择性miR-204过表达逆转。压力超负荷后miR-204敲除小鼠心脏转录组学的生物信息学分析表明apelin受体（APJ）信号转导失调。我们发现，牵张诱导的细胞外信号调节激酶1/2（ERK 1/2）激活和肥大相关基因表达依赖于APJ，而这两种效应都受到miR-204水平的影响。动力蛋白抑制剂dynasore抑制牵张诱导的APJ内吞作用和ERK 1/2激活。相比之下，miR-204诱导的APJ内吞作用既不受发动蛋白抑制剂（dynasore和dyngo）的抑制，也不与ERK 1/2激活相关。我们发现miR-204增加ras相关结合蛋白的表达（例如，Rab 5a、Rab 7），其调节细胞内吞作用。我们的研究结果表明，miR-204调节APJ的运输，并赋予对压力过载诱导的CH/CD的抵抗力，并且增加miR-204可以抑制CH/CD的发展。miR-204调节APJ的运输，并赋予对压力超负荷诱导的心脏肥大和心功能不全的抵抗力。
MicroRNAs regulate cardiac hypertrophy development, which precedes and predicts the risk of heart failure. microRNA‐204‐5p (miR‐204) is well expressed in cardiomyocytes, but its role in developing cardiac hypertrophy and cardiac dysfunction (CH/CD) remains poorly understood. Methods: We performed RNA‐sequencing, echocardiographic, and molecular/morphometric analysis of the heart of mice lacking or overexpressing miR‐204 five weeks after trans‐aortic constriction (TAC). The neonatal rat cardiomyocytes, H9C2, and HEK293 cells were used to determine the mechanistic role of miR‐204. The stretch induces miR‐204 expression, and miR‐204 inhibits the stretch‐induced hypertrophic response of H9C2 cells. The mice lacking miR‐204 displayed a higher susceptibility to CH/CD during pressure overload, which was reversed by the adeno‐associated virus serotype‐9‐mediated cardioselective miR‐204 overexpression. Bioinformatic analysis of the cardiac transcriptomics of miR‐204 knockout mice following pressure overload suggested deregulation of apelin‐receptor (APJ) signalling. We found that the stretch‐induced extracellular signal‐regulated kinase 1/2 (ERK1/2) activation and hypertrophy‐related genes expression depend on the APJ, and both of these effects are subject to miR‐204 levels. The dynamin inhibitor dynasore inhibited both stretch‐induced APJ endocytosis and ERK1/2 activation. In contrast, the miR‐204‐induced APJ endocytosis was neither inhibited by dynamin inhibitors (dynasore and dyngo) nor associated with ERK1/2 activation. We find that the miR‐204 increases the expression of ras‐associated binding proteins (e.g., Rab5a, Rab7) that regulate cellular endocytosis. Our results show that miR‐204 regulates trafficking of APJ and confers resistance to pressure overload‐induced CH/CD, and boosting miR‐204 can inhibit the development of CH/CD. miR‐204 regulates trafficking of APJ and confers resistance to pressure overload‐induced cardiac hypertrophy and cardiac dysfunction.
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