Levosimendan mediates the BMP/Smad axis through upregulation of circUSP34-targeted miR-1298 to alleviate pulmonary hypertension.

IF 5.8 2区医学 Q1 Medicine Respiratory Research Pub Date : 2024-08-19 DOI:10.1186/s12931-024-02945-5

Qiang Meng, Linhong Song, Hui Wang, Gang Wang, Gengxu Zhou

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Abstract

Background: Pulmonary hypertension (PH) is a long-term disease that impacts approximately 1% of the world's population. Currently, levosimendan (Lev) is proposed for PH treatment. However, the mechanism of Lev in the treatment of PH is unknown.

Methods: We used hypoxia-induced pulmonary artery smooth muscle cells (PASMCs) to establish a PH cell model. A number of cell biology methods were performed to assay alterations in cell proliferation, migration and apoptosis after Lev treatment. qRT-PCR and WB were performed to test the levels of circUSP34 and miR-1298, and BMP/Smad protein respectively. In addition, the regulatory relationship between circUSP34 or BMPR2 with miR-1298 was verified through the use of double luciferase as well as RIP assay. In addition, we explored the regulatory effect of Lev on the circUSP34/miR-1298/BMP/Smad axis using a rat PH model.

Results: Our results demonstrate that Lev inhibited PASMCs cell proliferation, migration and promoted apoptosis exposed to hypoxia. In hypoxia-treated PASMCs, circUSP34 expression got downregulated while miR-1298 upregulated, whereas the addition with Lev resulted in upregulation of circUSP34 expression and downregulation of miR-1298 expression, indicating that circUSP34 can target and regulate miR-1298. In addition, miR-1298 targets and regulates the expression of BMPR2. In a rat PH model induced by hypoxia combined with SU5416, Lev upregulated circUSP34 targeting miR-1298-mediated BMP/Smad axis to alleviate the PH phenotype.

Conclusion: We have shown that Lev can be used as a therapeutic drug for PH patients, which works through the circUSP34/miR-1298/BMP/Smad axis to alleviate PH symptoms.

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左西孟旦通过上调circUSP34靶向miR-1298介导BMP/Smad轴，从而缓解肺动脉高压。

背景：肺动脉高压（PH）是一种长期疾病，影响着全球约 1%的人口。目前，左西孟旦（Lev）被提议用于治疗肺动脉高压。然而，Lev 治疗 PH 的机制尚不清楚：我们使用缺氧诱导的肺动脉平滑肌细胞（PASMCs）建立了 PH 细胞模型。方法：我们利用缺氧诱导的肺动脉平滑肌细胞（PASMC）建立了 PH 细胞模型，并采用多种细胞生物学方法检测了 Lev 治疗后细胞增殖、迁移和凋亡的变化。此外，我们还通过双荧光素酶和 RIP 试验验证了 circUSP34 或 BMPR2 与 miR-1298 之间的调控关系。此外，我们还利用大鼠PH模型探讨了Lev对circUSP34/miR-1298/BMP/Smad轴的调控作用：结果：我们的研究结果表明，Lev 可抑制缺氧条件下 PASMCs 细胞的增殖、迁移并促进其凋亡。在缺氧处理的 PASMCs 中，circUSP34 表达下调，miR-1298 表达上调，而加入 Lev 后，circUSP34 表达上调，miR-1298 表达下调，这表明 circUSP34 可靶向调控 miR-1298。此外，miR-1298 还能靶向调节 BMPR2 的表达。在缺氧与 SU5416 联合诱导的大鼠 PH 模型中，Lev 上调了靶向 miR-1298 介导的 BMP/Smad 轴的 circUSP34，从而缓解了 PH 表型：我们的研究表明，Lev可作为PH患者的治疗药物，通过circUSP34/miR-1298/BMP/Smad轴缓解PH症状。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Respiratory Research RESPIRATORY SYSTEM-

CiteScore

9.70

自引率

1.70%

发文量

314

审稿时长

4-8 weeks

期刊介绍： Respiratory Research publishes high-quality clinical and basic research, review and commentary articles on all aspects of respiratory medicine and related diseases. As the leading fully open access journal in the field, Respiratory Research provides an essential resource for pulmonologists, allergists, immunologists and other physicians, researchers, healthcare workers and medical students with worldwide dissemination of articles resulting in high visibility and generating international discussion. Topics of specific interest include asthma, chronic obstructive pulmonary disease, cystic fibrosis, genetics, infectious diseases, interstitial lung diseases, lung development, lung tumors, occupational and environmental factors, pulmonary circulation, pulmonary pharmacology and therapeutics, respiratory immunology, respiratory physiology, and sleep-related respiratory problems.