Department of Immunology and Rheumatology, Shengjing Hospital of China Medical University, Shenyang 110004, People's Republic of China.
Department of General Surgery, The Fourth Affiliated Hospital of China Medical University, Shenyang 110032, People's Republic of China.
Toxicol Appl Pharmacol. 2020 Jan 1;386:114827. doi: 10.1016/j.taap.2019.114827. Epub 2019 Nov 14.
Endothelial-mesenchymal transition (EndMT) is a frequent event in endothelial dysfunction, which is associated with pulmonary arterial hypertension (PAH). MiR-181 family members exert diverse effects in multiple biological processes. However, the relationships between miR-181b-5p (miR-181b) and EndMT in PAH are not well understood. In this study, Sprague-Dawley (SD) rats were injected with monocrotaline (MCT) to establish PAH model, and primary rat pulmonary arterial endothelial cells (rPAECs) were treated with TNF-α, TGFβ1 and IL-1β in combination to induce EndMT (I-EndMT). Then we explored miR-181b expression and examined its functional role in PAH. Our data showed that miR-181b was down-expressed in PAH, and its overexpression attenuated the hemodynamics, pulmonary vascular hypertrophy, right ventricular remodeling and EndMT process in MCT-induced PAH rats. In I-EndMT rPAECs, we observed that inducing miR-181b reversed the decrease of endothelial markers and increase of mesenchymal markers. However, knockdown of miR-181b induced similar effects to EndMT. In addition, endocan and TGFBR1 levels were also increased in EndMT, which were negatively regulated by miR-181b. Luciferase activity results indicated that endocan and TGFBR1 were direct target genes of miR-181b. In summary, our findings firstly demonstrate that the beneficial effect of miR-181b on PAH may be associated with endocan/TGFBR1-mediated EndMT, providing a new insight into the diagnosis and treatment of PAH.
内皮-间质转化（EndMT）是内皮功能障碍的常见事件，与肺动脉高压（PAH）有关。miR-181 家族成员在多种生物学过程中发挥着不同的作用。然而，miR-181b-5p（miR-181b）与 PAH 中的 EndMT 之间的关系尚不清楚。在这项研究中，Sprague-Dawley（SD）大鼠注射单环酸（MCT）建立 PAH 模型，并用 TNF-α、TGFβ1 和 IL-1β 联合处理原代大鼠肺动脉内皮细胞（rPAEC）诱导 EndMT（I-EndMT）。然后我们探讨了 miR-181b 的表达，并研究了其在 PAH 中的功能作用。我们的数据表明，miR-181b 在 PAH 中表达下调，过表达 miR-181b 可减轻 MCT 诱导的 PAH 大鼠的血液动力学、肺血管肥大、右心室重构和 EndMT 过程。在 I-EndMT rPAEC 中，我们观察到诱导 miR-181b 逆转了内皮标志物的减少和间质标志物的增加。然而，miR-181b 的敲低诱导了类似的 EndMT 效应。此外，在 EndMT 中，内参蛋白和 TGFBR1 水平也升高，miR-181b 负调控它们。荧光素酶活性结果表明，内参蛋白和 TGFBR1 是 miR-181b 的直接靶基因。总之，我们的研究结果首次表明，miR-181b 对 PAH 的有益作用可能与内参蛋白/TGFBR1 介导的 EndMT 有关，为 PAH 的诊断和治疗提供了新的思路。
