MicroRNA-483 amelioration of experimental pulmonary hypertension.

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.

• Authors: Jin Zhang, Yangyang He, Xiaosong Yan, Shanshan Chen, Ming He, Yuyang Lei, Jiao Zhang, Brendan Gongol, Mingxia Gu, Yifei Miao, Liang Bai, Xiaopei Cui, Xiaojian Wang, Yixin Zhang, Fenling Fan, Zhao Li, Yuan Shen, Chih-Hung Chou, Hsien-Da Huang, Atul Malhotra, Marlene Rabinovitch, Zhi-Cheng Jing, John Y-J Shyy
• Journal: EMBO molecular medicine (EMBO Mol Med) Vol. 12 Issue 5 Pg. e11303 (05 08 2020) ISSN: 1757-4684 [Electronic] England
• PMID: 32324970 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2020 The Authors. Published under the terms of the CC BY 4.0 license.

Chemical References

• MIRN483 microRNA, human
• MicroRNAs
• Monocrotaline

Topics

• Animals
• Disease Models, Animal
• Humans
• Hypertension, Pulmonary (genetics)
• Hypoxia
• MicroRNAs (genetics)
• Monocrotaline
• Rats