Loss of Cardiac microRNA-Mediated Regulation Leads to Dilated Cardiomyopathy and Heart Failure

RATIONALE: Heart failure is a deadly and devastating disease that places immense costs on an aging society. To develop therapies aimed at rescuing the failing heart, it is important to understand the molecular mechanisms underlying cardiomyocyte structure and function. OBJECTIVE: microRNAs are important regulators of gene expression, and we sought to define the global contributions made by microRNAs toward maintaining cardiomyocyte integrity. METHODS AND RESULTS: First, we performed deep sequencing analysis to catalog the miRNA population in the adult heart. Second, 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. CONCLUSIONS: 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 may ultimately be responsible for the dramatic cardiac phenotype seen in the absence of dgcr8. We report the miRNA composition of 6-8 week old murine heart. We performed deep sequencing analysis to catalog the miRNA population in the adult heart. 2 sample were sequenced.研究背景：心力衰竭是一种致命且极具破坏性的疾病，给老龄化社会带来了沉重的负担。为开发旨在挽救衰竭心脏的治疗方法，了解心肌细胞结构与功能背后的分子机制至关重要。研究目的：微小RNA（microRNAs）是基因表达的重要调控因子，本研究旨在明确微小RNA对维持心肌细胞完整性的整体调控贡献。方法与结果：首先，我们通过深度测序分析对成年心脏中的微小RNA群体进行编目；其次，我们在心肌细胞中遗传敲除了微小RNA生物发生所需机制的关键组分。对心脏微小RNA的深度测序显示，少量微小RNA呈现富集特征，其中miR-1占所有微小RNA的40%。对心肌细胞特异性敲除微小RNA生物发生所需基因dgcr8后，观察到完全外显的表型：首先出现左心室功能异常，随后进展为扩张型心肌病，并最终导致过早死亡。结论：上述研究结果揭示了微小RNA在成熟心肌细胞维持心脏功能中的关键作用，并提示在缺乏dgcr8的情况下，仅需少量微小RNA即可引发上述显著的心脏表型。本研究报道了6-8周龄小鼠心脏的微小RNA组成，通过深度测序分析对成年心脏中的微小RNA群体进行了编目，共完成2个样本的测序。