Sun Q Liu L Wang H Mandal J Khan P Hostettler KE Stolz D Tamm M Molino A Lardinois D Lu S Roth M 2017 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. application/pdf https://sonar.ch/global/documents/232341 eng info:eu-repo/semantics/altIdentifier/doi/10.1016/j.jaci.2016.11.013 info:eu-repo/semantics/altIdentifier/pmid/28081849 info:eu-repo/semantics/openAccess The Journal of allergy and clinical immunology. - 2017 Airway wall remodeling STAT1 extracellular signal-regulated kinase miR-19a primary airway smooth muscle cell protein arginine methyltransferase 1 Aged Aged, 80 and over Airway Remodeling Asthma Cells, Cultured Collagen Type I Female Fibrinogen Humans Lung Male MicroRNAs Middle Aged Mitogen-Activated Protein Kinase 1 Mitogen-Activated Protein Kinase 3 Myocytes, Smooth Muscle Protein-Arginine N-Methyltransferases RNA, Messenger Repressor Proteins STAT1 Transcription Factor 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. http://purl.org/coar/resource_type/c_6501