IL-33 promotes the progression of nonrheumatic aortic valve stenosis via inducing differential phenotypic transition in valvular interstitial cells
IL-33 promotes the progression of nonrheumatic aortic valve stenosis via inducing differential phenotypic transition in valvular interstitial cells
复制标题
IL-33通过诱导瓣膜间质细胞差异表型转变促进非风湿性主动脉瓣狭窄的进展
DOI：
10.1016/j.jjcc.2019.06.011
复制
发表时间：
2020-02-01
影响因子：
2.5
通讯作者：
Lu, Li-ming
中科院分区：
文献类型：
--
作者：
He, Yu-bin;Guo, Jiang-hong;Lu, Li-ming
目的：白细胞介素（IL）-33在多种炎症性疾病的发病机制中起重要作用。其受体ST 2在非风湿性主动脉瓣狭窄（NR-AS）中过表达。这项研究比较了平滑肌α-肌动蛋白本研究通过检测NR-AS纤维化期和钙化期标本中α-SMA、骨桥蛋白（OPN）和致瘤性抑制因子2（ST 2）的表达，观察IL-33对猪瓣膜间质细胞（VIC）表型转化的影响及其机制。采用实时定量聚合酶链反应（RT-qPCR）和酶联免疫吸附试验（ELISA）检测NR-AS患者和健康成人外周血IL-1家族mRNA和蛋白水平。采用免疫组化和免疫荧光法检测NR-AS标本中α-SMA、OPN和ST 2的表达及共表达。用IL-33、IL-33+ SB 203580或IL-33+ SC 75741刺激猪VIC。结果：NR-AS患者外周血IL-33和sST 2的mRNA和蛋白水平均高于健康成人，且随着病程的延长，IL-33和sST 2的mRNA和蛋白水平逐渐升高。免疫组织化学和免疫荧光显示，NR-AS钙化期α-SMA、OPN和ST 2的表达高于纤维化期。ST 2/α-SMA或ST 2/OPN的共表达仅见于钙化期。核因子（NF）-κ B和p38丝裂原活化蛋白激酶（MAPK）磷酸化水平分别与IL-33诱导的猪维克血管内皮细胞分化为肌成纤维细胞和成骨细胞有关。IL-33刺激还可促进ST 2/OPN或α-SMA/OPN/ST 2的共表达。结论：IL-33可能是NR-AS的潜在生物标志物。IL-33诱导的猪维克血管内皮细胞分化为肌成纤维细胞和成骨细胞分别依赖于NF κ B和p38 MAPK信号通路。(C)2019年日本心脏病学院。由爱思唯尔有限公司出版。保留所有权利。
Objective: Interleukin (IL)-33 is a mediator in the pathogenesis of several inflammatory diseases. Its receptor, ST2, is overexpressed in nonrheumatic aortic valve stenosis (NR-AS). This study compared smooth muscle alpha-actin (alpha-SMA), osteopontin (OPN), and suppression of tumorigenicity 2 (ST2) expression between specimens from fibrotic and calcific stages of NR-AS and observed the effects and mechanisms of phenotypic transition of porcine valvular interstitial cells (VICs) in the presence of IL-33.Methods: Peripheral blood IL-1 family mRNA and protein levels in NR-AS patients and healthy adults were quantified by real-time quantitative polymerase chain reaction (RT-qPCR) and enzyme-linked immunosorbent assay. Immunohistochemistry and immunofluorescence were used to detect the expression and coexpression of alpha-SMA, OPN, and ST2 in NR-AS specimens. Porcine VICs were stimulated with IL-33, IL-33+SB203580, or IL-33+SC75741. mRNA and protein expression levels of porcine VICs were detected by RT-qPCR and western blot.Results: The mRNA and protein levels of IL-33 and sST2 in peripheral blood of NR-AS patients were higher than those in healthy adults. Immunohistochemistry and immunofluorescence showed higher expression of alpha-SMA, OPN, and ST2 in the calcific stage of NR-AS than in the fibrotic stage. Coexpression of ST2/alpha-SMA or ST2/OPN was found only in the calcific stage. Nuclear factor (NF)-kappa B and p38 mitogen-activated protein kinase (MAPK) phosphorylation levels were associated with IL-33-induced porcine VIC differentiation into myofibroblasts and osteoblasts, respectively. IL-33 stimulation also promoted the coexpression of ST2/OPN or alpha-SMA/OPN/ST2.Conclusion: IL-33 might be a potential biomarker for NR-AS. IL-33-induced porcine VIC differential phenotypic transition and differentiation into myofibroblasts and osteoblasts were dependent on the NFkB and p38 MAPK signaling pathways, respectively. (C) 2019 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.