Loss of cardiac microRNA-mediated regulation leads to dilated cardiomyopathy and heart failure.
Loss of cardiac microRNA-mediated regulation leads to dilated cardiomyopathy and heart failure.
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DOI：
10.1161/circresaha.109.200451
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发表时间：
2009-09-11
影响因子：
20.1
通讯作者：
Blelloch R
中科院分区：
文献类型：
--
作者：
Rao PK;Toyama Y;Chiang HR;Gupta S;Bauer M;Medvid R;Reinhardt F;Liao R;Krieger M;Jaenisch R;Lodish HF;Blelloch R
心力衰竭是一种致命的、毁灭性的疾病，给老龄化社会带来巨大的损失。为了开发旨在挽救衰竭心脏的疗法，了解心肌细胞结构和功能的分子机制非常重要。 microRNA 是基因表达的重要调节因子，我们试图确定 microRNA 对维持心肌细胞完整性所做出的全球贡献。首先，我们进行深度测序分析，对成人心脏中的 miRNA 群体进行分类。其次，我们在心肌细胞中基因删除了生成 miRNA 所需的机制的重要组成部分。对心脏 miRNA 的深度测序显示，少数 microRNA 中富集了一种 miR-1，占所有 microRNA 的 40%。心肌细胞特异性删除 dgcr8（microRNA 生物发生所需的基因），揭示了一种完全渗透的表型，该表型始于左心室功能障碍，进展为扩张型心肌病和过早死亡。这些观察结果揭示了 microRNA 在维持成熟心肌细胞心脏功能方面的关键作用，并提出了一种可能性，即只有少数 microRNA 可能最终导致在缺乏 dgcr8 的情况下出现的引人注目的心脏表型。
Heart failure is a deadly and devastating disease that places immense costs on an aging society. In order to develop therapies aimed at rescuing the failing heart, it is important to understand the molecular mechanisms underlying cardiomyocyte structure and function. microRNAs are important regulators of gene expression and we sought to define the global contributions made by microRNAs toward maintaining cardiomyocyte integrity. First, we performed deep sequencing analysis to catalog the miRNA population in the adult heart. Secondly, we genetically deleted, in cardiac myocytes, an essential component of the machinery that is required to generate miRNAs. Deep sequencing of miRNAs from the heart revealed the enrichment of a small number of microRNAs with one, miR-1, accounting for 40% of all microRNAs. Cardiomyocyte-specific deletion of dgcr8, a gene required for microRNA biogenesis, revealed a fully penetrant phenotype that begins with left ventricular malfunction progressing to a dilated cardiomyopathy and premature lethality. These observations reveal a critical role for microRNAs in maintaining cardiac function in mature cardiomyocytes and raise the possibility that only a handful of microRNAs maybe ultimately be responsible for the dramatic cardiac phenotype seen in the absence of dgcr8.