MicroRNA-212-5p, an anti-proliferative miRNA, attenuates hypoxia and sugen/hypoxia-induced pulmonary hypertension in rodents.
MicroRNA-212-5p, an anti-proliferative miRNA, attenuates hypoxia and sugen/hypoxia-induced pulmonary hypertension in rodents.
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DOI：
10.1016/j.omtn.2022.06.008
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发表时间：
2022-09-13
期刊：
影响因子：
--
通讯作者：
Raj, J. Usha
中科院分区：
文献类型：
--
作者：
Chen, Tianji;Sun, Miranda R.;Zhou, Qiyuan;Guzman, Alyssa M.;Ramchandran, Ramaswamy;Chen, Jiwang;Fraidenburg, Dustin R.;Ganesh, Balaji;Maienschein-Cline, Mark;Obrietan, Karl;Raj, J. Usha
MicroRNA（miRNA、miR-）在疾病发展中发挥着重要作用。在这项研究中，我们鉴定了一种抗增殖 miRNA，即 miR-212-5p，它是在肺动脉高压 (PH) 患者和实验性 PH 啮齿动物的肺动脉平滑肌细胞 (PASMC) 和肺部中诱导产生的。我们发现平滑肌细胞（SMC）特异性敲除 miR-212-5p 会加剧小鼠缺氧诱导的肺血管重塑和 PH，这表明 miR-212-5p 可能在 PASMC 中上调，作为 PH 的内源抑制剂，可能是通过抑制 PASMC 增殖来实现的。最近，细胞外囊泡（EV）被证明是有前途的疾病治疗药物递送工具。我们生成了富含 miR-212-5p 负载的内皮源性 EV 212-eEV，并发现它们显着减弱了小鼠缺氧诱导的 PH 和 Sugen/缺氧诱导的大鼠严重肺动脉高压，这为工程化内皮源性 EV 可用于将 miRNA 递送至肺部以治疗严重肺动脉高压提供了概念证明。 miR-212-5p 在肺动脉高压 (PH) 中发挥保护作用。给予外源性 miR-212-5p 显着减弱啮齿动物模型中的 PH，表明 miR-212-5p 可能是 PH 的潜在治疗靶点。我们还提供了第一个概念证明，即细胞外囊泡可以成为治疗 PH 的有前途的药物递送工具。
MicroRNAs (miRNA, miR-) play important roles in disease development. In this study, we identified an anti-proliferative miRNA, miR-212-5p, that is induced in pulmonary artery smooth muscle cells (PASMCs) and lungs of pulmonary hypertension (PH) patients and rodents with experimental PH. We found that smooth muscle cell (SMC)-specific knockout of miR-212-5p exacerbated hypoxia-induced pulmonary vascular remodeling and PH in mice, suggesting that miR-212-5p may be upregulated in PASMCs to act as an endogenous inhibitor of PH, possibly by suppressing PASMC proliferation. Extracellular vesicles (EVs) have been shown recently to be promising drug delivery tools for disease treatment. We generated endothelium-derived EVs with an enriched miR-212-5p load, 212-eEVs, and found that they significantly attenuated hypoxia-induced PH in mice and Sugen/hypoxia-induced severe PH in rats, providing proof of concept that engineered endothelium-derived EVs can be used to deliver miRNA into lungs for treatment of severe PH. miR-212-5p plays a protective role in pulmonary hypertension (PH). Administration of exogenous miR-212-5p significantly attenuates PH in rodent models, suggesting that miR-212-5p can be a potential therapeutic target for PH. We also provided the first proof of concept that extracellular vesicles can be a promising drug delivery tool for PH treatment.
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