title: MicroRNA-124 controls the proliferative, migratory, and inflammatory phenotype of pulmonary vascular fibroblasts.
abstract: BACKGROUND
  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.
  
  
  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.
authors.affiliation: From the Department of Pediatrics (D.W., H.Z., M.L., M.G.F., A.R.F., B.A.K., M.E.Y., M.A.F.), Department of Medicine (T.A.M., C.C.S.), Department of Medicine and Pediatrics (K.R.S.), Department of Medicine (N.W.M.), Department of Lung Development and Remodeling (S.S.P., S.V., W.S.), Department of Medicine (H.Z.), University of Colorado Anschutz Medical Campus, Aurora, CO; University of Cambridge, Cambridge, United Kingdom (N.W.M.); Addenbrooke's & Papworth Hospitals, Cambridge, United Kingdom (N.W.M.); Max-Planck-Institute for Heart and Lung Research; University of Giessen and Marburg Lung Center, Bad Nauheim, Germany (S.S.P., S.V., W.S.); and Shengjing Hospital of China Medical University, Shenyang, China (H.Z.).
authors.forename: Daren
authors.initials: D
authors.lastname: Wang
authors.forename: Hui
authors.initials: H
authors.lastname: Zhang
authors.forename: Min
authors.initials: M
authors.lastname: Li
authors.forename: Maria G
authors.initials: MG
authors.lastname: Frid
authors.forename: Amanda R
authors.initials: AR
authors.lastname: Flockton
authors.forename: B Alexandre
authors.initials: BA
authors.lastname: McKeon
authors.forename: Michael E
authors.initials: ME
authors.lastname: Yeager
authors.forename: Mehdi A
authors.initials: MA
authors.lastname: Fini
authors.forename: Nicholas W
authors.initials: NW
authors.lastname: Morrell
authors.forename: Soni S
authors.initials: SS
authors.lastname: Pullamsetti
authors.forename: Sivareddy
authors.initials: S
authors.lastname: Velegala
authors.forename: Werner
authors.initials: W
authors.lastname: Seeger
authors.forename: Timothy A
authors.initials: TA
authors.lastname: McKinsey
authors.forename: Carmen C
authors.initials: CC
authors.lastname: Sucharov
authors.forename: Kurt R
authors.initials: KR
authors.lastname: Stenmark
mesh_terms: D020413:3' Untranslated Regions; D000328:Adult; D000818:Animals; D002417:Cattle; D002465:Cell Movement; D049109:Cell Proliferation; D018932:Chemokine CCL2 / Q000235:genetics / Q000378:metabolism; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000235:genetics / Q000378:metabolism; D065627:Familial Primary Pulmonary Hypertension; D005260:Female; D005347:Fibroblasts / Q000378:metabolism* / Q000502:physiology; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D006976:Hypertension, Pulmonary / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D007249:Inflammation / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D010641:Phenotype; D038941:Polypyrimidine Tract-Binding Protein / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding; D011651:Pulmonary Artery / Q000378:metabolism / Q000473:pathology; D051381:Rats; D017208:Rats, Wistar; D051881:Receptor, Notch1 / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D014158:Transcription, Genetic
chemical_list: D020413:3' Untranslated Regions; D018932:Chemokine CCL2; D050759:Cyclin-Dependent Kinase Inhibitor p21; D051858:Forkhead Transcription Factors; C509207:MIRN124 microRNA, human; C548144:MIRN124 microRNA, rat; D035683:MicroRNAs; C540079:Mirn124 microRNA, mouse; D051881:Receptor, Notch1; D038941:Polypyrimidine Tract-Binding Protein; D050760:Cyclin-Dependent Kinase Inhibitor p27; D006655:Histone Deacetylases
keywords: anoxia; hypertension, pulmonary; migration; neoplasms; proliferation