MicroRNA-124 controls the proliferative, migratory, and inflammatory phenotype of pulmonary vascular fibroblasts

Circ Res. 2014 Jan 3;114(1):67-78. doi: 10.1161/CIRCRESAHA.114.301633. Epub 2013 Oct 11.


Rationale: Pulmonary hypertensive remodeling is characterized by excessive proliferation, migration, and proinflammatory activation of adventitial fibroblasts. In culture, fibroblasts maintain a similar activated phenotype. The mechanisms responsible for generation/maintenance of this phenotype remain unknown.

Objective: We hypothesized that aberrant expression of microRNA-124 (miR-124) regulates this activated fibroblast phenotype and sought to determine the signaling pathways through which miR-124 exerts effects.

Methods and results: We detected significant decreases in miR-124 expression in fibroblasts isolated from calves and humans with severe pulmonary hypertension. Overexpression of miR-124 by mimic transfection significantly attenuated proliferation, migration, and monocyte chemotactic protein-1 expression of hypertensive fibroblasts, whereas anti-miR-124 treatment of control fibroblasts resulted in their increased proliferation, migration, and monocyte chemotactic protein-1 expression. Furthermore, the alternative splicing factor, polypyrimidine tract-binding protein 1, was shown to be a direct target of miR-124 and to be upregulated both in vivo and in vitro in bovine and human pulmonary hypertensive fibroblasts. The effects of miR-124 on fibroblast proliferation were mediated via direct binding to the 3' untranslated region of polypyrimidine tract-binding protein 1 and subsequent regulation of Notch1/phosphatase and tensin homolog/FOXO3/p21Cip1 and p27Kip1 signaling. We showed that miR-124 directly regulates monocyte chemotactic protein-1 expression in pulmonary hypertension/idiopathic pulmonary arterial hypertension fibroblasts. Furthermore, we demonstrated that miR-124 expression is suppressed by histone deacetylases and that treatment of hypertensive fibroblasts with histone deacetylase inhibitors increased miR-124 expression and decreased proliferation and monocyte chemotactic protein-1 production.

Conclusions: Stable decreases in miR-124 expression contribute to an epigenetically reprogrammed, highly proliferative, migratory, and inflammatory phenotype of hypertensive pulmonary adventitial fibroblasts. Thus, therapies directed at restoring miR-124 function, including histone deacetylase inhibitors, should be investigated.

Keywords: anoxia; hypertension, pulmonary; migration; neoplasms; proliferation.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • 3' Untranslated Regions
  • Adult
  • Animals
  • Cattle
  • Cell Movement*
  • Cell Proliferation*
  • Chemokine CCL2 / genetics
  • Chemokine CCL2 / metabolism
  • Cyclin-Dependent Kinase Inhibitor p21 / genetics
  • Cyclin-Dependent Kinase Inhibitor p21 / metabolism
  • Cyclin-Dependent Kinase Inhibitor p27 / genetics
  • Cyclin-Dependent Kinase Inhibitor p27 / metabolism
  • Familial Primary Pulmonary Hypertension
  • Female
  • Fibroblasts / metabolism*
  • Fibroblasts / physiology
  • Forkhead Transcription Factors / genetics
  • Forkhead Transcription Factors / metabolism
  • Histone Deacetylases / metabolism
  • Humans
  • Hypertension, Pulmonary / genetics
  • Hypertension, Pulmonary / metabolism*
  • Hypertension, Pulmonary / pathology
  • Inflammation / metabolism
  • Male
  • Mice, Inbred C57BL
  • MicroRNAs / genetics
  • MicroRNAs / metabolism*
  • Phenotype
  • Polypyrimidine Tract-Binding Protein / genetics
  • Polypyrimidine Tract-Binding Protein / metabolism
  • Protein Binding
  • Pulmonary Artery / metabolism
  • Pulmonary Artery / pathology
  • Rats
  • Rats, Wistar
  • Receptor, Notch1 / genetics
  • Receptor, Notch1 / metabolism
  • Signal Transduction
  • Transcription, Genetic


  • 3' Untranslated Regions
  • Chemokine CCL2
  • Cyclin-Dependent Kinase Inhibitor p21
  • Forkhead Transcription Factors
  • MIRN124 microRNA, human
  • MIRN124 microRNA, rat
  • MicroRNAs
  • Mirn124 microRNA, mouse
  • Receptor, Notch1
  • Polypyrimidine Tract-Binding Protein
  • Cyclin-Dependent Kinase Inhibitor p27
  • Histone Deacetylases