蛋白精氨酸甲基转移酶 1 在哮喘气道平滑肌细胞中的组成性高表达是由于 microRNA-19a 表达降低引起的，并导致重塑增强。
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.
机构信息
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.
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.
出版信息
J Allergy Clin Immunol. 2017 Aug;140(2):510-524.e3. doi: 10.1016/j.jaci.2016.11.013. Epub 2017 Jan 9.
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.
背景
在哮喘重塑中，气道平滑肌细胞（ASMC）通过增殖、迁移和细胞外基质沉积导致气道壁增厚。先前，我们描述了蛋白质精氨酸甲基转移酶 1（PRMT1）参与 E3 大鼠肺部炎症中的气道重塑。
目的
我们旨在确定 PRMT1 在人 ASMC 中哮喘特异性调节机制。
方法
用血小板衍生生长因子（PDGF）-BB 激活来自健康受试者和哮喘患者的 ASMC。通过免疫组化在人肺组织切片中定位 PRMT1，并通过免疫荧光在分离的 ASMC 中定位。通过泛 PRMT 抑制剂 AMI-1 抑制 PRMT1 活性，通过小干扰 RNA 抑制信号转导和转录激活因子 1（STAT1），通过 PD98059 抑制细胞外信号调节激酶（ERK）1/2 丝裂原激活蛋白激酶（MAPK）。通过实时定量 PCR 评估 microRNAs（miRs），并通过 miR 模拟物或抑制剂进行调节。
结果
在严重哮喘患者的肺组织切片和分离的 ASMC 中，PRMT1 表达明显增加。PDGF-BB 通过 ERK1/2 MAPK 和 STAT1 信号在对照 ASMC 中显著增加 PRMT1 表达，而在哮喘患者的 ASMC 中，这些蛋白是组成性表达的。哮喘患者的 ASMC 中 miR-19a 表达减少，导致 ERK1/2 MAPK、STAT1 和 PRMT1 上调。抑制 PRMT1 可消除胶原 I 型和纤维连接蛋白沉积、ASMC 增殖和迁移。
结论
PRMT1 是哮喘患者 ASMC 组织重塑的核心调节剂，通过 PDGF-BB-miR-19a-ERK1/2 MAPK 和 STAT1 途径。哮喘患者 ASMC 中 miR-19a 表达降低是导致 PRMT1 表达和重塑持续增加的关键事件。因此，PRMT1 是限制哮喘患者气道壁重塑的一个有吸引力的靶点。
Zotero 插件