Division of Cardiovascular and Medical Sciences, British Heart Foundation Glasgow Cardiovascular Research Centre, 126 University Ave, University of Glasgow, Glasgow, Scotland.
Arterioscler Thromb Vasc Biol. 2010 Apr;30(4):716-23. doi: 10.1161/ATVBAHA.109.202028. Epub 2010 Jan 28.
MicroRNAs (miRNAs) are small noncoding RNAs that have the capacity to control protein production through binding "seed" sequences within a target mRNA. Each miRNA is capable of potentially controlling hundreds of genes. The regulation of miRNAs in the lung during the development of pulmonary arterial hypertension (PAH) is unknown.
We screened lung miRNA profiles in a longitudinal and crossover design during the development of PAH caused by chronic hypoxia or monocrotaline in rats. We identified reduced expression of Dicer, involved in miRNA processing, during the onset of PAH after hypoxia. MiR-22, miR-30, and let-7f were downregulated, whereas miR-322 and miR-451 were upregulated significantly during the development of PAH in both models. Differences were observed between monocrotaline and chronic hypoxia. For example, miR-21 and let-7a were significantly reduced only in monocrotaline-treated rats. MiRNAs that were significantly regulated were validated by quantitative polymerase chain reaction. By using in vitro studies, we demonstrated that hypoxia and growth factors implicated in PAH induced similar changes in miRNA expression. Furthermore, we confirmed miR-21 downregulation in human lung tissue and serum from patients with idiopathic PAH.
Defined miRNAs are regulated during the development of PAH in rats. Therefore, miRNAs may contribute to the pathogenesis of PAH and represent a novel opportunity for therapeutic intervention.
微小 RNA（miRNAs）是一类小的非编码 RNA，通过与靶 mRNA 中的“种子”序列结合，具有控制蛋白质产生的能力。每个 miRNA 都有可能控制数百个基因。肺内 miRNA 在肺动脉高压（PAH）发展过程中的调控尚不清楚。
我们采用慢性低氧或野百合碱诱导大鼠 PAH 的纵向和交叉设计筛选肺 miRNA 谱。我们发现，低氧诱导 PAH 发病时 miRNA 加工相关的 Dicer 表达降低。miR-22、miR-30 和 let-7f 在两种模型的 PAH 发展过程中均显著下调，而 miR-322 和 miR-451 则显著上调。野百合碱和慢性低氧之间存在差异。例如，仅在野百合碱处理的大鼠中，miR-21 和 let-7a 显著降低。通过定量聚合酶链反应验证了显著调节的 miRNAs。通过体外研究，我们证明了低氧和与 PAH 相关的生长因子诱导了 miRNA 表达的相似变化。此外，我们还证实了 miR-21 在特发性 PAH 患者的肺组织和血清中的下调。
在大鼠 PAH 发展过程中，特定的 miRNAs 受到调节。因此，miRNAs 可能有助于 PAH 的发病机制，并为治疗干预提供了新的机会。
