Jiang Jing, Xia Yimeng, Liang Yi, Yang Meiling, Zeng Wen, Zeng Xiaocong
Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi 530021, People's Republic of China.
Department of Anesthesiology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200025, People's Republic of China.
Int J Chron Obstruct Pulmon Dis. 2018 Nov 20;13:3777-3790. doi: 10.2147/COPD.S182504. eCollection 2018.
miR-190a-5p expression alters dynamically in response to hypoxia. However, the role of miR-190a-5p expression in hypoxia-induced pulmonary hypertension (PH) remains unclear. We sought to correlate the miR-190a-5p expression levels with the severity, diagnosis, and prognosis of PH in relation to chronic obstructive pulmonary disease (COPD-PH). Additionally, we evaluated the effect of miR-190a-5p through in vitro experiments on human pulmonary endothelial cells (HPECs) that were exposed to hypoxia and in vivo experiments using an animal model of hypoxia-induced PH.
Circulating miR-190a-5p levels were measured from 73 patients with PH and 32 healthy controls through quantitative real-time PCR. The levels of miR-190a-5p and the expression of Krüppel-like factor 15 (KLF15) were analyzed in HPECs that were exposed to hypoxia, and the effects of antagomir-190a-5p in mice with chronic hypoxia-induced PH were tested. Target gene analysis was performed by Western blot and luciferase assay.
The miR-190a-5p level was significantly higher in patients with COPD-PH than in the healthy controls. Higher miR-190a-5p levels were associated with a greater severity of COPD-PH. In vitro experiments on HPECs showed that exposure to hypoxia increased the miR-190a-5p levels significantly. KLF15 was validated as a target of miR-190a-5p. Transfection with miR-190a-5p mimicked inhibition of KLF15 expression in HPECs. In the mouse model of PH, antagomir-190a-5p reduced right ventricular systolic pressure and enhanced the KLF15 expression levels in lung tissue.
miR-190a-5p regulates hypoxia-induced PH by targeting KLF15. The circulating levels of miR-190a-5p correlate with the severity of COPD-PH, thereby confirming the diagnostic and prognostic value of this parameter in COPD-PH.
miR-190a-5p的表达会因缺氧而动态变化。然而，miR-190a-5p表达在缺氧诱导的肺动脉高压（PH）中的作用仍不清楚。我们试图将miR-190a-5p的表达水平与慢性阻塞性肺疾病相关性肺动脉高压（COPD-PH）的严重程度、诊断及预后联系起来。此外，我们通过体外实验研究了miR-190a-5p对缺氧的人肺内皮细胞（HPECs）的影响，并通过体内实验，利用缺氧诱导的PH动物模型进行了评估。
通过定量实时PCR检测了73例PH患者和32例健康对照者循环中的miR-190a-5p水平。分析了缺氧的HPECs中miR-190a-5p的水平及Krüppel样因子15（KLF15）的表达，并检测了抗miR-190a-5p对慢性缺氧诱导的PH小鼠的影响。通过蛋白质印迹法和荧光素酶测定进行靶基因分析。
COPD-PH患者的miR-?190a-5p水平显著高于健康对照者。较高的miR-190a-5p水平与COPD-PH的更严重程度相关。对HPECs的体外实验表明，缺氧显著增加了miR-190a-5p水平。KLF15被确认为miR-190a-5p的靶标。用miR-190a-5p模拟物转染可模拟对HPECs中KLF15表达的抑制。在PH小鼠模型中，抗miR-190a-5p降低了右心室收缩压，并提高了肺组织中KLF15的表达水平。
miR-190a-5p通过靶向KLF15调节缺氧诱导的PH。miR-190a-5p的循环水平与COPD-PH的严重程度相关，从而证实了该参数在COPD-PH中的诊断和预后价值。
