MiR-125a-5p ameliorates monocrotaline-induced pulmonary arterial hypertension by targeting the TGF-β1 and IL-6/STAT3 signaling pathways.
MiR-125a-5p ameliorates monocrotaline-induced pulmonary arterial hypertension by targeting the TGF-β1 and IL-6/STAT3 signaling pathways.
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MiR-125a-5p 通过靶向 TGF-β 1 和 IL-6/STAT3 信号通路改善野百合碱诱导的肺动脉高压
DOI：
10.1038/s12276-018-0068-3
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发表时间：
2018-04-27
影响因子：
12.8
通讯作者：
Shen J
中科院分区：
文献类型：
--
作者：
Cai Z;Li J;Zhuang Q;Zhang X;Yuan A;Shen L;Kang K;Qu B;Tang Y;Pu J;Gou D;Shen J
由于肺动脉平滑肌细胞（PASMC）过度增殖和抗凋亡导致的肺血管重塑是肺动脉高压（PAH）的标志性特征。最近的证据表明 miR-125a-5p 在野百合碱诱导的 PAH (MCT-PAH) 大鼠模型中发挥作用；然而，其根本机制目前尚不清楚。在这里，我们检查了 MCT-PAH 大鼠中 miR-125a-5p 的表达谱，并使用 miR-125a-5p agomir 研究了 miR-125a-5p 的假定治疗效果。此外，将miR-125a-5p agomir或antagomir转染至大鼠PASMC中，并测量增殖和凋亡。使用荧光素酶报告基因测定测量 miR-125a-5p 靶标 STAT3 的活性，并使用 RT-qPCR 和/或蛋白质印迹分析测量下游分子的表达。重要的是，诱导体内 miR-125a-5p 表达通过降低肺动脉收缩压、富尔顿指数和肺血管重塑来减缓 MCT-PAH 的进展。此外，过表达miR-125a-5p可抑制PASMCs的增殖并促进其凋亡。此外，用TGF-β1或IL-6刺激PASMCs上调miR-125a-5p表达，而过表达miR-125a-5p则减少TGF-β1和IL-6的产生及其下游靶标STAT3和Smad2/3的表达；相反，下调 miR-125a-5p 会增加 TGF-β1 和 IL-6 的产生。最后，双荧光素酶报告基因检测显示 miR-125a-5p 靶向 STAT3 的 3'-UTR，抑制下游分子 PCNA、Bcl-2 和 Survivin。综上所述，这些研究结果表明，miR-125a-5p 可改善大鼠的 MCT-PAH，与 TGF-β1 和 IL-6 具有负反馈调节作用，并通过直接靶向 STAT3 来调节 PASMC 的增殖和凋亡。一项针对大鼠的研究表明，小 RNA 分子 miR-125a-5p 是治疗肺动脉高压 (PAH) 的有希望的治疗靶点。这种类型的高血压是由于将血液从心脏输送到肺部的动脉狭窄所致，目前尚无治愈方法。中国上海交通大学的 Jieyan Shen 及其同事发现，PAH 降低了大鼠肺动脉中 miR-125a-5p 的水平，并且将 miR-125a-5p 作为早期预防性治疗可减少疾病进展。 miR-125a-5p通过直接与基因表达调节剂相互作用并减少某些促炎信号分子的产生来减缓肺动脉平滑肌细胞的增殖并引发细胞死亡。针对 miR-125a-5p 的作用机制可能代表一种治疗这种改变生活的慢性疾病的新方法。
Pulmonary vascular remodeling due to excessive proliferation and resistance to apoptosis of pulmonary artery smooth muscle cells (PASMCs) is the hallmark feature of pulmonary arterial hypertension (PAH). Recent evidence suggests that miR-125a-5p plays a role in a rat model of monocrotaline-induced PAH (MCT-PAH); however, the underlying mechanism is currently unknown. Here, we examined the expression profile of miR-125a-5p in MCT-PAH rats and investigated the putative therapeutic effect of miR-125a-5p using the miR-125a-5p agomir. In addition, the miR-125a-5p agomir or antagomir was transfected into rat PASMCs, and proliferation and apoptosis were measured. Activity of the miR-125a-5p target STAT3 was measured using a luciferase reporter assay, and the expression of downstream molecules was measured using RT–qPCR and/or western blot analysis. Importantly, inducing miR-125a-5p expression in vivo slowed the progression of MCT-PAH by reducing systolic pulmonary arterial pressure, the Fulton index, and pulmonary vascular remodeling. Moreover, overexpressing miR-125a-5p inhibited the proliferation and promoted the apoptosis of PASMCs. In addition, stimulating PASMCs with TGF-β1 or IL-6 upregulated miR-125a-5p expression, whereas overexpressing miR-125a-5p reduced TGF-β1 and IL-6 production, as well as the expression of their downstream targets STAT3 and Smad2/3; in contrast, downregulating miR-125a-5p increased TGF-β1 and IL-6 production. Finally, a dual-luciferase reporter assay revealed that miR-125a-5p targets the 3′-UTR of STAT3, suppressing the downstream molecules PCNA, Bcl-2, and Survivin. Taken together, these findings suggest that miR-125a-5p ameliorates MCT-PAH in rats, has a negative feedback regulation with TGF-β1 and IL-6, and regulates the proliferation and apoptosis of PASMCs by directly targeting STAT3. A study in rats suggests that the small RNA molecule miR-125a-5p is a promising therapeutic target for treating pulmonary arterial hypertension (PAH). This type of high blood pressure is due to the narrowing of arteries that carry blood from the heart to the lungs and at present has no cure. Jieyan Shen at Shanghai Jiao Tong University, China, and colleagues found that PAH lowers the levels of miR-125a-5p in rat pulmonary arteries and that administration of miR-125a-5p as an early preventative treatment reduced disease progression. miR-125a-5p slowed the proliferation of pulmonary artery smooth muscle cells and triggered cell death by directly interacting with a gene expression regulator and reducing the production of certain pro-inflammatory signaling molecules. Targeting miR-125a-5p’s mechanism of action could represent a new treatment approach for this chronic, life-changing disease.
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DOI：
10.1016/j.echo.2015.08.018
发表时间：
2016-02-01
影响因子：
6.5
作者：
Shen, Jie-yan;Cai, Zong-ye;He, Ben
通讯作者：
He, Ben
影响因子：
24
作者：
Tuder, Rubin M.;Archer, Stephen L.;Dorfmueller, Peter;Erzurum, Serpil C.;Guignabert, Christophe;Michelakis, Evangelos;Rabinovitch, Marlene;Schermuly, Ralph;Stenmark, Kurt R.;Morrell, Nicholas W.
通讯作者：
Morrell, Nicholas W.
DOI：
10.1152/ajplung.00309.2011
发表时间：
2012-03-01
影响因子：
4.9
作者：
Davies, Rachel J.;Holmes, Alan M.;Morrell, Nicholas W.
通讯作者：
Morrell, Nicholas W.
影响因子：
37.8
作者：
Long, Lu;Crosby, Alexi;Morrell, Nicholas W.
通讯作者：
Morrell, Nicholas W.
影响因子：
3.9
作者：
Zhang, Hongqiao;Davies, Kelvin J. A.;Forman, Henry Jay
通讯作者：
Forman, Henry Jay