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Cell Tissue Res. 2017 Sep;369(3):527-539. doi: 10.1007/s00441-017-2625-9. Epub 2017 May 8.

MicroRNA-27a/b mediates endothelin-1-induced PPARγ reduction and proliferation of pulmonary artery smooth muscle cells.

Author information

1
Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Medical College, Xi'an Jiaotong University, No.277, Yanta West Road, Xi'an, Shaanxi, People's Republic of China, 710061.
2
Division of Allergy and Clinical Immunology, Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD, 21224, USA.
3
Department of Pharmacology, School of Basic Medical Sciences, Xian Jiaotong University Health Science Center, Xi'an, Shaanxi, People's Republic of China, 710061.
4
Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Medical College, Xi'an Jiaotong University, No.277, Yanta West Road, Xi'an, Shaanxi, People's Republic of China, 710061. manxiangli@hotmail.com.

Abstract

The down-regulation of peroxisome proliferator-activated receptor γ (PPARγ) expression has been found to correlate with the proliferation of pulmonary artery smooth muscle cells (PASMC), pulmonary vascular remodeling and pulmonary hypertension, while the molecular mechanisms underlying PPARγ reduction in PASMC remain largely unclear. The aim of the current study is to address this issue. Endothelin-1 (ET-1) dose- and time-dependently resulted in PPARγ reduction and proliferation of primary cultured rat PASMC, which was accompanied by the activation of nuclear factor-kappaB (NF-κB) and subsequent induction of microRNA-27a/b (miR-27a/b) expression. Chromatin immunoprecipitation assay revealed that NF-κB directly bound to the promoter regions of miR-27a/b. Luciferase reporter assay identified that miR-27a/b directly regulates the expression of PPARγ in PASMC. Further study indicated that the presence of either NF-κB inhibitor pyrrolidinedithiocarbamate or prior silencing miR-27a/b with anti-miRNA oligonucleotides suppressed ET-1-induced PPARγ reduction and proliferation of PASMC, while overexpression of miR-27a/b reduced PPARγ expression and enhanced PASMC proliferation. Taken together, our study demonstrates that ET-1 stimulates miR-27a/b expression by activation of the NF-κB pathway, which in turn results in PPARγ reduction and contributes to ET-1-induced PASMC proliferation.

KEYWORDS:

Endothelin-1; Nuclear factor-kappaB; Peroxisome proliferator-activated receptor γ; Pulmonary artery smooth muscle cells; Pulmonary hypertension; miR-27a/b

PMID:
28484848
DOI:
10.1007/s00441-017-2625-9
[Indexed for MEDLINE]

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