Endothelial dysfunction plays a central role in the pathophysiology of pulmonary arterial hypertension (PAH). MicroRNAs (miRNAs) are small single-strand and non-coding RNAs that negatively regulate gene function by binding to the 3′-untranslated region (3′-UTR) of specific mRNAs. microRNA-1 (miR-1) is upregulated in plasma from idiopathic PAH patients and in lungs from an experimental model of PAH. However, the role of miRNA-1 on endothelial dysfunction is unknown. The aim of this study was to analyze the effects of miR-1 on endothelial function in rat pulmonary arteries (PA). Endothelial function was studied in PA from PAH or healthy animals and mounted in a wire myograph. Some PA from control animals were transfected with miR-1 or scramble miR. Superoxide anion production by miR-1 was quantified by dihydroethidium (DHE) fluorescence in rat PA smooth muscle cells (PASMC). Bioinformatic analysis identified superoxide dismutase-1 (SOD1), connexin-43 (Cx43), caveolin 2 (CAV2) and Krüppel-like factor 4 (KLF4) as potential targets of miR-1. The expression of SOD1, Cx43, CAV2, and KLF4 was determined by qRT-PCR and western blot in PASMC. PA incubated with miR-1 presented decreased endothelium-dependent relaxation to acetylcholine. We also found an increase in the production of O₂⁻ and decreased expression of SOD1, Cx43, CAV2, and KLF4 in PASMC induced by miR-1, which may contribute to endothelial dysfunction. In conclusion, these data indicate that miR-1 induces endothelial dysfunction, suggesting a pathophysiological role in PAH.

中文翻译：

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miR-1诱导大鼠肺动脉内皮功能障碍。

内皮功能障碍在肺动脉高压（PAH）的病理生理中起着核心作用。MicroRNA（miRNA）是小的单链和非编码RNA，它们通过与特定mRNA的3'-非翻译区（3'-UTR）结合而负调控基因功能。特发性PAH患者的血浆和PAH实验模型的肺中的microRNA-1（miR-1）上调。但是，miRNA-1在内皮功能障碍中的作用尚不清楚。这项研究的目的是分析miR-1对大鼠肺动脉（PA）内皮功能的影响。在PAH或健康动物的PA中研究了内皮功能，并将其安装在钢丝肌电图仪中。用miR-1或扰乱miR转染一些来自对照动物的PA。通过大鼠PA平滑肌细胞（PASMC）中的二氢乙啶（DHE）荧光定量测定miR-1产生的超氧阴离子。生物信息学分析确定超氧化物歧化酶1（SOD1），连接蛋白43（Cx43），小窝蛋白2（CAV2）和克虏伯样因子4（KLF4）是miR-1的潜在靶标。通过qRT-PCR和western blot检测PASMC中SOD1，Cx43，CAV2和KLF4的表达。与miR-1孵育的PA呈现出降低的内皮依赖性舒张性。我们还发现O的产量增加了 与miR-1孵育的PA呈现出降低的内皮依赖性舒张性。我们还发现O的产量增加了 与miR-1孵育的PA呈现出降低的内皮依赖性舒张性。我们还发现O的产量增加了₂ ^-和在PASMC受miR-1诱导，这可能有助于内皮功能障碍SOD1，Cx43的，CAV2，和KLF4的表达减少。总之，这些数据表明miR-1诱导了内皮功能障碍，提示在PAH中的病理生理作用。