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MicroRNA‐483 amelioration of experimental pulmonary hypertension
- Zhang, Jin;
- He, Yangyang;
- Yan, Xiaosong;
- Chen, Shanshan;
- He, Ming;
- Lei, Yuyang;
- Zhang, Jiao;
- Gongol, Brendan;
- Gu, Mingxia;
- Miao, Yifei;
- Bai, Liang;
- Cui, Xiaopei;
- Wang, Xiaojian;
- Zhang, Yixin;
- Fan, Fenling;
- Li, Zhao;
- Shen, Yuan;
- Chou, Chih‐Hung;
- Huang, Hsien‐Da;
- Malhotra, Atul;
- Rabinovitch, Marlene;
- Jing, Zhi‐Cheng;
- Shyy, John Y‐J
- et al.
Published Web Location
https://doi.org/10.15252/emmm.201911303Abstract
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-β (TGF-β), TGF-β receptor 2 (TGFBR2), β-catenin, connective tissue growth factor (CTGF), interleukin-1β (IL-1β), and endothelin-1 (ET-1). Overexpression of miR-483 in ECs inhibited inflammatory and fibrogenic responses, revealed by the decreased expression of TGF-β, TGFBR2, β-catenin, CTGF, IL-1β, 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.
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