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Cell and Tissue Research

, Volume 369, Issue 3, pp 527–539 | Cite as

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

  • Xinming Xie
  • Shaojun Li
  • Yanting Zhu
  • Lu Liu
  • Yilin Pan
  • Jian Wang
  • Wenhua Shi
  • Yang Song
  • Lan Yang
  • Li Gao
  • Weijin Zang
  • Manxiang LiEmail author
Regular Article

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 miR-27a/b Peroxisome proliferator-activated receptor γ Pulmonary artery smooth muscle cells Pulmonary hypertension 

Abbreviations

BrdU

5-Bromo-29-deoxyuridine

ChIP

Chromatin immunoprecipitation

DMEM

Dulbecco’s Modified Eagle Medium

EC

Endothelial cell

EDTA

Ethylene diamine tetraacetic acid

ET-1

Endothelin-1

FBS

Fetal bovine serum

GAPDH

Glyceraldehyde-3-phosphate dehydrogenase

miR

MicroRNA

NC

Negative control

NF-κB

Nuclear factor-kappaB

NP-40

Nonidet P-40

PAECs

Pulmonary arterial endothelial cells

PH

Pulmonary hypertension

PAP

Pulmonary arterial pressure

PASMC

Pulmonary artery smooth muscle cells

PCR

Polymerase chain reaction

PDTC

Pyrrolidine dithiocarbamate

PMSF

Phenylmethylsulfonyl fluoride

PPARγ

Peroxisome proliferator-activated receptor γ

SDS

Sodium dodecyl sulfate

UTR

Untranslated region

Notes

Acknowledgement

This study was supported by the National Natural Science Foundation of China (Grant No. 81070045).

Compliance with ethical standards

The funders of this project had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Competing interests

The authors have declared no conflict of interest.

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Copyright information

© Springer-Verlag Berlin Heidelberg 2017

Authors and Affiliations

  • Xinming Xie
    • 1
  • Shaojun Li
    • 1
  • Yanting Zhu
    • 1
  • Lu Liu
    • 1
  • Yilin Pan
    • 1
  • Jian Wang
    • 1
  • Wenhua Shi
    • 1
  • Yang Song
    • 1
  • Lan Yang
    • 1
  • Li Gao
    • 2
  • Weijin Zang
    • 3
  • Manxiang Li
    • 1
    Email author
  1. 1.Department of Respiratory and Critical Care Medicine, The First Affiliated Hospital of Medical CollegeXi’an Jiaotong UniversityXi’anPeople’s Republic of China
  2. 2.Division of Allergy and Clinical Immunology, Department of MedicineThe Johns Hopkins University School of MedicineBaltimoreUSA
  3. 3.Department of Pharmacology, School of Basic Medical SciencesXian Jiaotong University Health Science CenterXi’anPeople’s Republic of China

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