期刊
EMBO MOLECULAR MEDICINE
卷 12, 期 5, 页码 -出版社
WILEY
DOI: 10.15252/emmm.201911303
关键词
miR-483; endothelium; pulmonary hypertension; TGF-beta
资金
- Beijing Natural Science Foundation [7181009]
- 13th Five-Year Plan-Precise Medicine-Key Research and Development Program-Clinical Cohort of Rare Disease [2016YFC0901500]
- Key Project of Natural Science Foundation of China [81630003]
- CAMS Innovation Fund for Medical Sciences [2016-I2M-1-002, 2017-I2M-BR-02]
- National Natural Science Foundation of China [81270349, 81670452]
- Beijing Nova Programme Interdisciplinary Cooperation Project [XXJC201805-Z181100006218125]
- NIH [K24 HL132105, K99 HL135258]
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.
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