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MicroRNA-483 amelioration of experimental pulmonary hypertension.

  • Author(s): 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.
Abstract

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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