High-mobility group box-1 protein induces osteogenic phenotype changes in aortic valve interstitial cells
High-mobility group box-1 protein induces osteogenic phenotype changes in aortic valve interstitial cells
复制标题
高迁移率group box-1蛋白诱导主动脉瓣间质细胞成骨表型变化
DOI：
10.1016/j.jtcvs.2015.09.077
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发表时间：
2016-01-01
影响因子：
6
通讯作者：
Dong, Nianguo
中科院分区：
文献类型：
--
作者：
Wang, Bo;Li, Fei;Dong, Nianguo
目的：钙化性主动脉瓣（AV）疾病是一种炎症相关疾病。高迁移率族蛋白1（HMGB 1）和Toll样受体4（TLR 4）参与了多种炎症性疾病的发生。本研究旨在探讨HMGB 1-TLR 4轴是否参与钙化性房室结疾病的发生，并探讨HMGB 1对钙化性房室结瓣膜间质细胞（VIC）成骨表型的影响及其可能机制。将培养的VIC用作体外模型。用HMGB 1刺激VIC进行分析，用与不用TLR 4小干扰核糖核酸（siRNA）、c-Jun N-末端激酶促分裂原活化蛋白激酶（JNK MAPK）和核因子κ-B（NF-κ B）抑制剂。此外，我们发现HMGB 1诱导高水平的促炎细胞因子的产生，并促进成骨细胞分化和钙化的VIC。此外，HMGB 1还可诱导JNK MAPK和NF-κ B B磷酸化。然而，这些作用被TLR 4的siRNA沉默显著抑制。结论：HMGB 1蛋白可能通过TLR 4-JNK-NF-kappa B信号通路促进VICs的成骨分化和钙化。
Objectives: Calcific aortic valve (AV) disease is known to be an inflammation-related process. High-mobility group box-1 (HMGB1) protein and Toll-like receptor 4 (TLR4) have been reported to participate in several inflammatory diseases. The purpose of the present study was to determine whether the HMGB1-TLR4 axis is involved in calcific AV disease, and to evaluate the effect of HMGB1, and its potential mechanisms, on the pro-osteogenic phenotype change of valvular interstitial cells (VICs).Methods: Expression of HMGB1 and TLR4 in human calcific AVs was evaluated using immunohistochemical staining and immunoblotting. Cultured VICs were used as an in vitro model. The VICs were stimulated with HMGB1 for analysis, with versus without TLR4 small interfering ribonucleic acid (siRNA), c-Jun N-terminal kinase mitogen-activated protein kinase (JNK MAPK), and nuclear factor kappa-B (NF-kappa B) inhibitors.Results: Enhanced accumulation of HMGB1 and TLR4 was observed in calcific valves. Moreover, we found that HMGB1 induced high levels of pro-inflammatory cytokine production and promoted the osteoblastic differentiation and calcification of VICs. In addition, HMGB1 induced phosphorylation of JNK MAPK and NF-kappa B. However, these effects were markedly suppressed by siRNA silencing of TLR4. In addition, blockade of JNK MAPK and NF-kappa B phosphorylation prohibited HMGB1-induced production of pro-osteogenic factors, and mineralization of VICs.Conclusions: The HMGB1 protein may promote osteoblastic differentiation and calcification of VICs, through the TLR4-JNK-NF-kappa B signaling pathway.