MicroRNA-27a/b mediates endothelin-1-induced PPARγ reduction and proliferation of pulmonary artery smooth muscle cells
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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.
KeywordsEndothelin-1 Nuclear factor-kappaB miR-27a/b Peroxisome proliferator-activated receptor γ Pulmonary artery smooth muscle cells Pulmonary hypertension
Dulbecco’s Modified Eagle Medium
Ethylene diamine tetraacetic acid
Fetal bovine serum
Pulmonary arterial endothelial cells
Pulmonary arterial pressure
Pulmonary artery smooth muscle cells
Polymerase chain reaction
Peroxisome proliferator-activated receptor γ
Sodium dodecyl sulfate
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.
The authors have declared no conflict of interest.
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