title: Constitutive high expression of protein arginine methyltransferase 1 in asthmatic airway smooth muscle cells is caused by reduced microRNA-19a expression and leads to enhanced remodeling.
abstract: BACKGROUND
  In asthma remodeling airway smooth muscle cells (ASMCs) contribute to airway wall thickness through increased proliferation, migration, and extracellular matrix deposition. Previously, we described that protein arginine methyltransferase 1 (PRMT1) participates in airway remodeling in pulmonary inflammation in E3 rats.
  
  
  OBJECTIVE
  We sought to define the asthma-specific regulatory mechanism of PRMT1 in human ASMCs.
  
  
  METHODS
  ASMCs from healthy subjects and asthmatic patients were activated with platelet-derived growth factor (PDGF)-BB. PRMT1 was localized by means of immunohistochemistry in human lung tissue sections and by means of immunofluorescence in isolated ASMCs. PRMT1 activity was suppressed by the pan-PRMT inhibitor AMI-1, signal transducer and activator of transcription 1 (STAT1) was suppressed by small interfering RNA, and extracellular signal-regulated kinase (ERK) 1/2 mitogen-activated protein kinase (MAPK) was suppressed by PD98059. MicroRNAs (miRs) were assessed by using real-time quantitative PCR and regulated by miR mimics or inhibitors.
  
  
  RESULTS
  PRMT1 expression was significantly increased in lung tissue sections and in isolated ASMCs of patients with severe asthma. PDGF-BB significantly increased PRMT1 expression through ERK1/2 MAPK and STAT1 signaling in control ASMCs, whereas in ASMCs from asthmatic patients, these proteins were constitutively expressed. ASMCs from asthmatic patients had reduced miR-19a expression, causing upregulation of ERK1/2 MAPK, STAT1, and PRMT1. Inhibition of PRMT1 abrogated collagen type I and fibronectin deposition, cell proliferation, and migration of ASMCs from asthmatic patients.
  
  
  CONCLUSIONS
  PRMT1 is a central regulator of tissue remodeling in ASMCs from asthmatic patients through the pathway: PDGF-BB-miR-19a-ERK1/2 MAPK and STAT1. Low miR-19a expression in ASMCs from asthmatic patients is the key event that results in constitutive increased PRMT1 expression and remodeling. Therefore PRMT1 is an attractive target to limit airway wall remodeling in asthmatic patients.
authors.affiliation: Department of Biochemistry and Molecular Biology, Key Laboratory of Environment and Genes Related to Diseases (Ministry of Education), Xi'an Jiaotong University Health Science Center, Xi'an, China; Pneumology and Pulmonary Cell Research, Department of Biomedicine, University of Basel and University Hospital Basel, Basel, Switzerland.
authors.forename: Qingzhu
authors.initials: Q
authors.lastname: Sun
authors.affiliation: Department of Biochemistry and Molecular Biology, Key Laboratory of Environment and Genes Related to Diseases (Ministry of Education), Xi'an Jiaotong University Health Science Center, Xi'an, China.
authors.forename: Li
authors.initials: L
authors.lastname: Liu
authors.affiliation: Stem Cells and Hematopoiesis, Department of Biomedicine, University of Basel and University Hospital Basel, Basel, Switzerland.
authors.forename: Hui
authors.initials: H
authors.lastname: Wang
authors.affiliation: Pneumology and Pulmonary Cell Research, Department of Biomedicine, University of Basel and University Hospital Basel, Basel, Switzerland.
authors.forename: Jyotshna
authors.initials: J
authors.lastname: Mandal
authors.affiliation: Pneumology and Pulmonary Cell Research, Department of Biomedicine, University of Basel and University Hospital Basel, Basel, Switzerland.
authors.forename: Petra
authors.initials: P
authors.lastname: Khan
authors.affiliation: Pneumology and Pulmonary Cell Research, Department of Biomedicine, University of Basel and University Hospital Basel, Basel, Switzerland.
authors.forename: Katrin E
authors.initials: KE
authors.lastname: Hostettler
authors.affiliation: Pneumology and Pulmonary Cell Research, Department of Biomedicine, University of Basel and University Hospital Basel, Basel, Switzerland.
authors.forename: Daiana
authors.initials: D
authors.lastname: Stolz
authors.affiliation: Pneumology and Pulmonary Cell Research, Department of Biomedicine, University of Basel and University Hospital Basel, Basel, Switzerland.
authors.forename: Michael
authors.initials: M
authors.lastname: Tamm
authors.affiliation: Department of Respiratory Diseases, University of Naples, Federico II, Naples, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Molino
authors.affiliation: Department of Thoracic Surgery, University Hospital Basel, Basel, Switzerland.
authors.forename: Didier
authors.initials: D
authors.lastname: Lardinois
authors.affiliation: Department of Biochemistry and Molecular Biology, Key Laboratory of Environment and Genes Related to Diseases (Ministry of Education), Xi'an Jiaotong University Health Science Center, Xi'an, China.
authors.forename: Shemin
authors.initials: S
authors.lastname: Lu
authors.affiliation: Pneumology and Pulmonary Cell Research, Department of Biomedicine, University of Basel and University Hospital Basel, Basel, Switzerland. Electronic address: Michael.roth@usb.ch.
authors.forename: Michael
authors.initials: M
authors.lastname: Roth
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D056151:Airway Remodeling; D001249:Asthma / Q000378:metabolism* / Q000473:pathology*; D002478:Cells, Cultured; D024042:Collagen Type I / Q000378:metabolism; D005260:Female; D005340:Fibrinogen / Q000378:metabolism; D006801:Humans; D008168:Lung / Q000378:metabolism / Q000473:pathology; D008297:Male; D035683:MicroRNAs / Q000378:metabolism*; D008875:Middle Aged; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000378:metabolism; D011484:Protein-Arginine N-Methyltransferases / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D050794:STAT1 Transcription Factor / Q000378:metabolism
chemical_list: D024042:Collagen Type I; C549214:MIRN19A microRNA, human; D035683:MicroRNAs; D012333:RNA, Messenger; D012097:Repressor Proteins; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D005340:Fibrinogen; C099988:PRMT1 protein, human; D011484:Protein-Arginine N-Methyltransferases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3
keywords: Airway wall remodeling; STAT1; extracellular signal-regulated kinase; miR-19a; primary airway smooth muscle cell; protein arginine methyltransferase 1