title: MicroRNA-143 Activation Regulates Smooth Muscle and Endothelial Cell Crosstalk in Pulmonary Arterial Hypertension.
abstract: BACKGROUND
  The pathogenesis of pulmonary arterial hypertension (PAH) remains unclear. The 4 microRNAs representing the miR-143 and miR-145 stem loops are genomically clustered.
  
  
  OBJECTIVE
  To elucidate the transcriptional regulation of the miR-143/145 cluster and the role of miR-143 in PAH.
  
  
  RESULTS
  We identified the promoter region that regulates miR-143/145 microRNA expression in pulmonary artery smooth muscle cells (PASMCs). We mapped PAH-related signaling pathways, including estrogen receptor, liver X factor/retinoic X receptor, transforming growth factor-β (Smads), and hypoxia (hypoxia response element), that regulated levels of all pri-miR stem loop transcription and resulting microRNA expression. We observed that miR-143-3p is selectively upregulated compared with miR-143-5p during PASMC migration. Modulation of miR-143 in PASMCs significantly altered cell migration and apoptosis. In addition, we found high abundance of miR-143-3p in PASMC-derived exosomes. Using assays with pulmonary arterial endothelial cells, we demonstrated a paracrine promigratory and proangiogenic effect of miR-143-3p-enriched exosomes from PASMC. Quantitative polymerase chain reaction and in situ hybridization showed elevated expression of miR-143 in calf models of PAH and in samples from PAH patients. Moreover, in contrast to our previous findings that had not supported a therapeutic role in vivo, we now demonstrate a protective role of miR-143 in experimental pulmonary hypertension in vivo in miR-143-/- and anti-miR-143-3p-treated mice exposed to chronic hypoxia in both preventative and reversal settings.
  
  
  CONCLUSIONS
  MiR-143-3p modulated both cellular and exosome-mediated responses in pulmonary vascular cells, whereas inhibition of miR-143-3p blocked experimental pulmonary hypertension. Taken together, these findings confirm an important role for the miR-143/145 cluster in PAH pathobiology.
authors: Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, G12 8TA, UK.
authors: Lin
authors: L
authors: Deng
authors: Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, G12 8TA, UK.
authors: Francisco J
authors: FJ
authors: Blanco
authors: Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, G12 8TA, UK.
authors: Hannah
authors: H
authors: Stevens
authors: Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, G12 8TA, UK.|King's British Heart Foundation Centre, King's College London, 125 Coldharbour Lane, London SE59NU, United Kingdom.
authors: Ruifang
authors: R
authors: Lu
authors: Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, G12 8TA, UK.
authors: Axelle
authors: A
authors: Caudrillier
authors: Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, G12 8TA, UK.
authors: Martin
authors: M
authors: McBride
authors: Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, G12 8TA, UK.
authors: John D
authors: JD
authors: McClure
authors: Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, G12 8TA, UK.
authors: Jenny
authors: J
authors: Grant
authors: Novartis Institutes for BioMedical Research, Horsham UK.|AstraZeneca R&D Mölndal, R&D | Respiratory, Inflammation and Autoimmunity (RIA) Innovative Medicines, Building AC461, SE-431 83 Mölndal, Sweden.
authors: Matthew
authors: M
authors: Thomas
authors: Division of Critical Care Medicine/Cardiovascular Pulmonary Research Laboratories, Department of Pediatrics and Medicine, University of Colorado Denver, Aurora, CO 80045, USA.
authors: Maria
authors: M
authors: Frid
authors: Division of Critical Care Medicine/Cardiovascular Pulmonary Research Laboratories, Department of Pediatrics and Medicine, University of Colorado Denver, Aurora, CO 80045, USA.
authors: Kurt
authors: K
authors: Stenmark
authors: Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, G12 8TA, UK.|Novartis Institutes for BioMedical Research, Inc.,250 Massachusetts Avenue, Cambridge, MA 02139, United States.
authors: Kevin
authors: K
authors: White
authors: MiRagen Therapeutics, Inc, Boulder, CO.
authors: Anita G
authors: AG
authors: Seto
authors: Division of Respiratory Medicine, Department of Medicine, Addenbrooke's Hospital, University of Cambridge School of Clinical Medicine, Cambridge, CB2 0QQ, UK.
authors: Nicholas W
authors: NW
authors: Morrell
authors: Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, G12 8TA, UK.
authors: Angela C
authors: AC
authors: Bradshaw
authors: Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, G12 8TA, UK.
authors: Margaret R
authors: MR
authors: MacLean
authors: Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, G12 8TA, UK.
authors: Andrew H
authors: AH
authors: Baker
mesh_terms: D000818:Animals; D062186:Arterial Pressure; D001665:Binding Sites; D016022:Case-Control Studies; D002417:Cattle; D002450:Cell Communication; D002465:Cell Movement; D042783:Endothelial Cells / Q000378:metabolism* / Q000473:pathology; D055354:Exosomes / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation; D006367:HeLa Cells; D006801:Humans; D006976:Hypertension, Pulmonary / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D009131:Muscle, Smooth, Vascular / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D032389:Myocytes, Smooth Muscle / Q000378:metabolism* / Q000473:pathology; D011401:Promoter Regions, Genetic; D011651:Pulmonary Artery / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D015398:Signal Transduction; D013997:Time Factors; D014157:Transcription Factors / Q000378:metabolism; D014162:Transfection; D066253:Vascular Remodeling; D016278:Ventricular Function, Right; D017725:Ventricular Pressure
chemical_list: C542359:MIRN143 microRNA, human; C541010:MIRN145 microRNA, human; C543499:MIRN145a microRNA, mouse; D035683:MicroRNAs; C532884:MIRN143 microRNA, mouse; D014157:Transcription Factors
keywords: cell movement; endothelium; exosomes; hypertension, pulmonary; microRNAs; myocytes, smooth muscle