MicroRNA-34a regulates cardiac ageing and function
MicroRNA-34a regulates cardiac ageing and function
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DOI：
10.1038/nature11919
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发表时间：
2013-03-07
期刊：
影响因子：
64.8
通讯作者：
Dimmeler, Stefanie
中科院分区：
文献类型：
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作者：
Boon, Reinier A.;Iekushi, Kazuma;Dimmeler, Stefanie
老龄化是心血管疾病的主要风险因素（1），并导致急性心肌梗死患者的预后显著恶化（2）。MicroRNA（miRNAs）已成为心血管功能的重要调节因子，一些miRNAs在衰老中发挥关键作用（3，4）。我们认为，衰老过程中心脏中miRNA表达的改变有助于心脏功能的年龄依赖性下降。在这里，我们发现miR-34 a在衰老的心脏中被诱导，并且miR-34 a的体内沉默或基因缺失减少了与年龄相关的心肌细胞死亡。此外，miR-34 a抑制减少了急性心肌梗死后的细胞死亡和纤维化，并改善了心肌功能的恢复。从机制上讲，我们将PNUTS（也称为PPP 1 R10）确定为一种新的直接miR-34 a靶点，它可以减少端粒缩短，DNA损伤反应和心肌细胞凋亡，并改善急性心肌梗死后的功能恢复。总之，这些结果确定了年龄诱导的miR-34 a表达及其靶点PNUTS的抑制是衰老期间和急性心肌梗死后通过诱导DNA损伤反应和端粒磨损调节心脏收缩功能的关键机制。
Ageing is the predominant risk factor for cardiovascular diseases(1) and contributes to a significantly worse outcome in patients with acute myocardial infarction(2). MicroRNAs (miRNAs) have emerged as crucial regulators of cardiovascular function and some miRNAs have key roles in ageing(3,4). We propose that altered expression of miRNAs in the heart during ageing contributes to the age-dependent decline in cardiac function. Here we show that miR-34a is induced in the ageing heart and that in vivo silencing or genetic deletion of miR-34a reduces age-associated cardiomyocyte cell death. Moreover, miR-34a inhibition reduces cell death and fibrosis following acute myocardial infarction and improves recovery of myocardial function. Mechanistically, we identified PNUTS (also known as PPP1R10) as a novel direct miR-34a target, which reduces telomere shortening, DNA damage responses and cardiomyocyte apoptosis, and improves functional recovery after acute myocardial infarction. Together, these results identify age-induced expression of miR-34a and inhibition of its target PNUTS as a key mechanism that regulates cardiac contractile function during ageing and after acute myocardial infarction, by inducing DNA damage responses and telomere attrition.