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.
- Sun Q 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.
- Liu L 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.
- Wang H Stem Cells and Hematopoiesis, Department of Biomedicine, University of Basel and University Hospital Basel, Basel, Switzerland.
- Mandal J Pneumology and Pulmonary Cell Research, Department of Biomedicine, University of Basel and University Hospital Basel, Basel, Switzerland.
- Khan P Pneumology and Pulmonary Cell Research, Department of Biomedicine, University of Basel and University Hospital Basel, Basel, Switzerland.
- Hostettler KE Pneumology and Pulmonary Cell Research, Department of Biomedicine, University of Basel and University Hospital Basel, Basel, Switzerland.
- Stolz D Pneumology and Pulmonary Cell Research, Department of Biomedicine, University of Basel and University Hospital Basel, Basel, Switzerland.
- Tamm M Pneumology and Pulmonary Cell Research, Department of Biomedicine, University of Basel and University Hospital Basel, Basel, Switzerland.
- Molino A Department of Respiratory Diseases, University of Naples, Federico II, Naples, Italy.
- Lardinois D Department of Thoracic Surgery, University Hospital Basel, Basel, Switzerland.
- Lu S 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.
- Roth M Pneumology and Pulmonary Cell Research, Department of Biomedicine, University of Basel and University Hospital Basel, Basel, Switzerland. Electronic address: Michael.roth@usb.ch.
- 2017-01-14
Published in:
- 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
English
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.
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.
- Language
-
- English
- Open access status
- bronze
- Identifiers
-
- DOI 10.1016/j.jaci.2016.11.013
- PMID 28081849
- Persistent URL
- https://sonar.ch/global/documents/232341
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