miR-1 is increased in pulmonary hypertension and downregulates Kv1.5 channels in rat pulmonary arteries
miR-1 is increased in pulmonary hypertension and downregulates Kv1.5 channels in rat pulmonary arteries
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DOI：
10.1113/jp276054
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发表时间：
2019-02-15
影响因子：
5.5
通讯作者：
Perez-Vizcaino, Francisco
中科院分区：
文献类型：
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作者：
Mondejar-Parreno, Gema;Callejo, Maria;Perez-Vizcaino, Francisco
电压依赖性钾通道 (Kv) 的损伤在包括肺动脉高压 (PAH) 在内的心血管疾病的发展中起着核心作用。 MicroRNA 是非编码 RNA，通过与特定 mRNA 的 3 个非翻译区结合来调节基因表达。本研究旨在分析 miR-1 对肺动脉 (PA) Kv 通道功能的影响。研究了转染 miR-1 或乱序 miR 的健康动物的 PA 中的 Kv 通道活性。使用膜片钳技术的全细胞配置来研究 Kv 电流。 Kv1.5 电流的表征是使用选择性抑制剂 DPO-1 进行的。在缺氧和 Su5416 诱导的 PAH 大鼠模型中，肺中 miR-1 表达增加，Kv1.5 通道减少。 miR-1 转染增加了分离的肺动脉平滑肌细胞的细胞电容，减少了 Kv1.5 电流并诱导膜去极化。荧光素酶报告基因检测表明，编码 Kv1.5 通道的 KCNA5 是 miR-1 的直接靶基因。 PA 与 Su5416 和缺氧 (3% O-2) 一起孵育会增加 miR-1 并诱导 Kv1.5 电流下降，而 antagomiR-1 可以阻止这种情况。总之，这些数据表明 miR-1 诱导肺动脉平滑肌细胞肥大并降低 Kv 通道的活性和表达，表明其在 PAH 中具有病理生理学作用。
Impairment of the voltage-dependent potassium channel (Kv) plays a central role in the development of cardiovascular diseases, including pulmonary arterial hypertension (PAH). MicroRNAs are non-coding RNAs that regulate gene expression by binding to the 3-untranslated region region of specific mRNAs. The present study aimed to analyse the effects of miR-1 on Kv channel function in pulmonary arteries (PA). Kv channel activity was studied in PA from healthy animals transfected with miR-1 or scrambled-miR. Kv currents were studied using the whole-cell configuration of the patch clamp technique. The characterization of the Kv1.5 currents was performed with the selective inhibitor DPO-1. miR-1 expression was increased and Kv1.5 channels were decreased in lungs from a rat model of PAH induced by hypoxia and Su5416. miR-1 transfection increased cell capacitance, reduced Kv1.5 currents and induced membrane depolarization in isolated pulmonary artery smooth muscle cells. A luciferase reporter assay indicated that KCNA5, which encodes Kv1.5 channels, is a direct target gene of miR-1. Incubation of PA with Su5416 and hypoxia (3% O-2) increased miR-1 and induced a decline in Kv1.5 currents, which was prevented by antagomiR-1. In conclusion, these data indicate that miR-1 induces pulmonary artery smooth muscle cell hypertrophy and reduces the activity and expression of Kv channels, suggesting a pathophysiological role in PAH.