High mobility group box-1 induces migration of vascular smooth muscle cells via TLR4-dependent PI3K/Akt pathway activation
High mobility group box-1 induces migration of vascular smooth muscle cells via TLR4-dependent PI3K/Akt pathway activation
复制标题
DOI：
10.1007/s11033-011-1106-6
复制
发表时间：
2012-03-01
影响因子：
2.8
通讯作者：
Li, Xinxin
中科院分区：
文献类型：
--
作者：
Yang, Jian;Chen, Lihua;Li, Xinxin
高迁移率族蛋白1（HMGB 1）是一种有效的炎症介质，已知通过与多种细胞表面受体（包括TLR和TLR）结合来调节细胞事件。然而，TLR 4和HMGB 1信号转导在血管平滑肌细胞（VSMCs）迁移中的作用至今未见报道。本研究旨在探讨HMGB 1诱导的VSMCs迁移是通过TLR 4激活磷脂酰肌醇3激酶/Akt（PI 3 K/Akt）信号通路介导的假说。研究了大鼠胸主动脉VSMCs。HMGB 1（0.1-1000 ng/ml）以剂量依赖性方式刺激VSMCs迁移，最高值（约3.5倍）。用100 ng/ml孵育VSMC引起PI 3 K活性和Akt磷酸化的快速增加。TLR 4沉默可显著抑制VSMCs向HMGB 1的迁移（P < 0.05）。TLR 4 siRNA或PI 3 K抑制剂LY 294002预处理细胞后，可显著阻断HMGB 1介导的PI 3 K/Akt通路激活和VSMCs迁移（P均< 0.05）。结论：HMGB 1通过TLR 4依赖的PI 3 K/Akt信号通路诱导VSMCs迁移，提示HMGB 1可能参与血管损伤后再狭窄的新生内膜形成。
High mobility group box-1 (HMGB1), a potent mediator of inflammation, is known to regulate cellular events through binding to the multiple cell-surface receptors, including RAGE and TLRs. However, the role of TLR4 and details of HMGB1 signaling in vascular smooth muscle cells (VSMCs) migration has not been reported so far. The present study was designed to investigate the hypothesis that HMGB1-induced VSMCs migration is mediated via activation of phosphoinositide 3-kinase/Akt (PI3K/Akt) signalling pathway through TLR4. VSMCs from rat thoracic aorta were studied. HMGB1 (0.1-1000 ng/ml) stimulated VSMCs migration in a dose-dependent manner, with the highest value (about 3.5-fold increase). Incubation of VSMCs with 100 ng/ml caused a rapid increase in PI3K activity and Akt phosphorylation. Migration of VSMCs toward HMGB1 was significantly inhibited by silencing of TLR4 (P < 0.05). We also found pretreated cells with TLR4 siRNA or the PI3 K inhibitor LY294002 could markedly block PI3K/Akt pathway activation and VSMCs migration mediated by HMGB1 (P both < 0.05). In conclusion, HMGB1 induces migration of VSMCs through a TLR4-dependent PI3 K/Akt signaling pathway, which suggests a possible molecular mechanism for HMGB1 may contribute to neointima formation in restenosis after vascular damage.