MicroRNA-483 amelioration of experimental pulmonary hypertension
MicroRNA-483 amelioration of experimental pulmonary hypertension
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MicroRNA-483 改善实验性肺动脉高压
DOI：
10.15252/emmm.201911303
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发表时间：
2020-04-23
影响因子：
11.1
通讯作者：
Shyy, John Y-J
中科院分区：
文献类型：
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作者：
Zhang Jin;He Yangyang;Shyy, John Y-J
内皮功能障碍在肺动脉高压（PAH）的发病机制中起着关键作用，外源性microRNA可能具有治疗益处。在特发性肺动脉高压（IPAH）患者的血清中发现了较低水平的miR-483，特别是那些患有更严重疾病的患者。RNA-seq和生物信息学分析表明，miR-483靶向几个PAH相关基因，包括转化生长因子-β（TGF-β）、TGF-β受体2（TGFBR 2）、β-连环蛋白、结缔组织生长因子（CTGF）、白细胞介素-1 β（IL-1 β）和内皮素-1（ET-1）。内皮细胞中miR-483的过表达抑制了炎症和纤维化反应，表现为TGF-β、TGFBR 2、β-连环蛋白、CTGF、IL-1 β和ET-1的表达降低。相反，抑制miR-483增加了EC中的这些基因。EC特异性miR-483过表达的大鼠在用野百合碱（MCT）或Sugen +缺氧激发时表现出肺动脉高压（PH）改善和右心室肥大减轻。在接受MCT和吸入过表达miR-483的慢病毒的大鼠中观察到逆转效应。这些结果表明PAH与miR-483水平降低相关，并且miR-483可能通过抑制多种不良反应来降低实验PH。
Endothelial dysfunction is critically involved in the pathogenesis of pulmonary arterial hypertension (PAH) and that exogenously administered microRNA may be of therapeutic benefit. Lower levels of miR-483 were found in serum from patients with idiopathic pulmonary arterial hypertension (IPAH), particularly those with more severe disease. RNA-seq and bioinformatics analyses showed that miR-483 targets several PAH-related genes, including transforming growth factor-beta (TGF-beta), TGF-beta receptor 2 (TGFBR2), beta-catenin, connective tissue growth factor (CTGF), interleukin-1 beta (IL-1 beta), and endothelin-1 (ET-1). Overexpression of miR-483 in ECs inhibited inflammatory and fibrogenic responses, revealed by the decreased expression of TGF-beta, TGFBR2, beta-catenin, CTGF, IL-1 beta, and ET-1. In contrast, inhibition of miR-483 increased these genes in ECs. Rats with EC-specific miR-483 overexpression exhibited ameliorated pulmonary hypertension (PH) and reduced right ventricular hypertrophy on challenge with monocrotaline (MCT) or Sugen + hypoxia. A reversal effect was observed in rats that received MCT with inhaled lentivirus overexpressing miR-483. These results indicate that PAH is associated with a reduced level of miR-483 and that miR-483 might reduce experimental PH by inhibition of multiple adverse responses.