Inhibition of miR-21 improves pulmonary vascular responses in bronchopulmonary dysplasia by targeting the DDAH1/ADMA/NO pathway.
Inhibition of miR-21 improves pulmonary vascular responses in bronchopulmonary dysplasia by targeting the DDAH1/ADMA/NO pathway.
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DOI：
10.1515/med-2022-0584
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发表时间：
2022
期刊：
影响因子：
2.1
通讯作者：
Chen, Xiaoqing
中科院分区：
文献类型：
--
作者：
Zhong, Ying;Zhang, Zhiqun;Chen, Xiaoqing
已证实miR-21在患有高氧介导的支气管肺发育不良（BPD）的新生大鼠肺中过表达。miR-21在BPD中的具体功能尚不清楚。建立了高氧诱导的BPD大鼠体内模型和高氧诱导的肺微血管内皮细胞（PMVECs）体外模型。采用Transwell法检测PMVEC的迁移能力。试管形成实验检测血管生成能力。ELISA法检测细胞内、外一氧化氮（NO）含量及细胞内、外ADMA浓度。此外，miR-21和二甲基精氨酸二甲氨基水解酶1（DDAH 1）之间的相互作用进行了评估，使用荧光素酶报告基因分析。我们发现高氧刺激可增加PMVEC中miR-21的表达。抑制miR-21可提高PMVEC的迁移和血管生成活性，而过表达miR-21则产生相反的效果。此外，在高氧处理的PMVEC中，miR-21的敲低增加了NO的产生并降低了细胞内和细胞外ADMA的浓度。接下来，我们证明了miR-21可以与DDAH 1结合并负调控其表达。Rescues分析显示，DDAH 1敲低逆转了miR-21耗竭对高氧介导的PMVEC功能、NO产生和ADMA浓度的影响。重要的是，miR-21下调恢复了BPD大鼠的肺泡化和血管密度。这项研究表明，抑制miR-21通过靶向DDAH 1/ADMA/NO通路改善BPD的肺血管反应。
miR-21 has been confirmed to be overexpressed in neonatal rat lungs with hyperoxia-mediated bronchopulmonary dysplasia (BPD). The specific function of miR-21 in BPD is still unclear. We established the hyperoxia-induced BPD rat model in vivo and the hyperoxia-induced pulmonary microvascular endothelial cells (PMVECs) model in vitro. Transwell assay was utilized to detect the migratory capability of PMVECs. Tube formation assay was utilized to measure angiogenesis ability. ELISA was utilized to test nitric oxide (NO) production and the intracellular and extracellular Asymmetric Dimethylarginine (ADMA) concentration. Furthermore, the interaction between miR-21 and dimethylarginine dimethylaminohydrolase 1 (DDAH1) was evaluated using luciferase reporter assay. We found that miR-21 expression in PMVECs was increased by hyperoxia stimulation. Inhibition of miR-21 improved the migratory and angiogenic activities of PMVECs and overexpression of miR-21 exerted the opposite effects. Furthermore, knockdown of miR-21 increased NO production and decreased intracellular and extracellular ADMA concentration in hyperoxia-treated PMVECs. Next we proved that miR-21 could bind to DDAH1 and negatively regulate its expression. Rescues assays showed that DDAH1 knockdown reversed the effects of miR-21 depletion on hyperoxia-mediated PMVEC functions, NO production, and ADMA concentration. Importantly, miR-21 downregulation restored alveolarization and vascular density in BPD rats. This study demonstrates that inhibition of miR-21 improves pulmonary vascular responses in BPD by targeting the DDAH1/ADMA/NO pathway.
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DOI：
10.1152/ajplung.00316.2019
发表时间：
2020-02-01
影响因子：
4.9
作者：
Dolma, Kalsang;Freeman, Amelia E.;Lal, Charitharth Vivek
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影响因子：
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作者：
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DOI：
10.1016/j.bbrc.2006.08.115
发表时间：
2006-10-20
影响因子：
3.1
作者：
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Li, Yuan-Jian
影响因子：
6.8
作者：
Böger, RH
通讯作者：
Böger, RH