Elevated miR-499 levels blunt the cardiac stress response.
Elevated miR-499 levels blunt the cardiac stress response.
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DOI：
10.1371/journal.pone.0019481
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发表时间：
2011-05-09
期刊：
影响因子：
3.7
通讯作者：
Srivastava D
中科院分区：
文献类型：
--
作者：
Shieh JT;Huang Y;Gilmore J;Srivastava D
心脏通过精心描述的转录反应来应对无数的压力，这些转录反应涉及基因表达的长期变化以及更直接、更短暂的适应。MicroRNAs定量调节mRNAs，从而可能影响心脏转录输出和心功能。在这里，我们研究miR-499，一种嵌入在心肌和骨骼肌中表达的心室特异性肌球蛋白重链基因中的微RNA。我们评估了miR-499在人体组织中的表达，以确认其与人类心脏基因调控的潜在相关性。使用转基因小鼠模型，我们发现miR-499水平升高以剂量依赖的方式导致细胞肥大和心脏功能障碍。全球基因表达谱显示，即刻早期应激反应基因(Egr1、Egr2和Fos)、肌球蛋白重链(Myh7)和骨骼肌肌动蛋白(Acta1)的水平发生了变化。我们通过miR-499在体外获得和失去功能来验证miR-499对即刻早期反应基因的影响。与miR-499在钝化心脏应激反应中的作用一致，无症状miR-499表达的小鼠对压力超负荷的反应减弱，心功能障碍加重。MiR-499水平升高会影响心脏基因的表达，并易导致心脏应激引起的功能障碍。MIR-499可能部分通过调节即刻早期基因反应来滴定心脏对应激的反应。
The heart responds to myriad stresses by well-described transcriptional responses that involve long-term changes in gene expression as well as more immediate, transient adaptations. MicroRNAs quantitatively regulate mRNAs and thus may affect the cardiac transcriptional output and cardiac function. Here we investigate miR-499, a microRNA embedded within a ventricular-specific myosin heavy chain gene, which is expressed in heart and skeletal muscle. We assessed miR-499 expression in human tissue to confirm its potential relevance to human cardiac gene regulation. Using a transgenic mouse model, we found that elevated miR-499 levels caused cellular hypertrophy and cardiac dysfunction in a dose-dependent manner. Global gene expression profiling revealed altered levels of the immediate early stress response genes (Egr1, Egr2 and Fos), ß-myosin heavy chain (Myh7), and skeletal muscle actin (Acta1). We verified the effect of miR-499 on the immediate early response genes by miR-499 gain- and loss-of-function in vitro. Consistent with a role for miR-499 in blunting the response to cardiac stress, asymptomatic miR-499-expressing mice had an impaired response to pressure overload and accentuated cardiac dysfunction. Elevated miR-499 levels affect cardiac gene expression and predispose to cardiac stress-induced dysfunction. miR-499 may titrate the cardiac response to stress in part by regulating the immediate early gene response.