Leukotriene B4 mediates vascular smooth muscle cell migration through αvβ3 integrin transactivation
Leukotriene B4 mediates vascular smooth muscle cell migration through αvβ3 integrin transactivation
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DOI：
10.1016/j.atherosclerosis.2010.06.009
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发表时间：
2010-10-01
期刊：
影响因子：
5.3
通讯作者：
Barja-Fidalgo, Christina
中科院分区：
文献类型：
--
作者：
Moraes, Joao;Assreuy, Jamil;Barja-Fidalgo, Christina
血管损伤导致局部炎症反应，表现为内皮细胞损伤、细胞外基质外露以及血小板和循环白细胞的聚集/黏附。炎症介质的释放放大了这一过程，并可诱导血管平滑肌细胞(SMC)迁移和增殖。白三烯B-4(LTB4)由白细胞释放，可诱导活性氧的产生和SMC的趋化。本研究以大鼠血管SMC系(A7r5)为研究对象，探讨LTB4影响SMC迁移的分子机制。LTB4的趋化作用依赖于使用的浓度，与100 nm处的Angii相当。百日咳毒素、BLT1受体拮抗剂CP-105696和PI3K和MEK1/2的两种抑制剂LY294002或PD98059分别抑制LTB_4诱导的细胞迁移。LTB4刺激SMC可触发整合素相关信号通路，诱导粘着斑激酶(FAK)磷酸化，肌动蛋白细胞骨架活化，FAK与PI3K结合，ERK-2磷酸化和核转位，以及NF-kappa B通路的激活。αvβ3整合素的选择性配体Kistrin可抑制LTB4诱导的趋化作用、FAK磷酸化和FAK-PI3K结合，也可抑制ERK-2和NF-kappa B通路的激活。综上所述，这些数据首次证明LTB4对SMC迁移的影响是通过整合素信号激活来调节的，提示这些黏附分子可能是心血管疾病治疗干预的重要靶点。(C)2010爱思唯尔爱尔兰有限公司。保留所有权利。
Vascular injury leads to a local inflammatory response, characterized by endothelial damage, extracellular matrix exposition and aggregation/adhesion of platelets and circulating leukocytes. The release of inflammatory mediators amplifies the process, and can induce vascular smooth muscle cells (SMC) migration and proliferation. Released by leukocytes, leukotriene B-4 (LTB4) induces reactive oxygen species production and SMC chemotaxis. This study was conducted to elucidate the molecular mechanisms involved in the effect of LTB4 on SMC migration, and a rat linage of vascular SMC (A7r5) were used throughout. The chemotactic effect of LTB4 was dependent on the concentration used, being comparable to AngII at 100 nM. Migration induced by LTB4 was inhibited in the presence of pertussis toxin, CP-105696, a BLT1 receptor antagonist, and by LY294002 or PD98059, two inhibitors of PI3K and MEK1/2, respectively. Stimulation of SMC with LTB4 triggered integrin-associated signaling pathways, inducing focal adhesion kinase (FAK) phosphorylation, mobilization of actin cytoskeleton, association of FAK to PI3K, ERK-2 phosphorylation and nuclear translocation, and also NF kappa B pathway activation. Pretreatment of SMC with a selective ligand of alpha v beta 3 integrin, kistrin, inhibited LTB4-induced chemotaxis, FAK phosphorylation, FAK-PI3K association, and also inhibited ERK-2 and NF kappa B pathways activation. Taken together, the data demonstrated, for the first time, that the effect of LTB4 on SMC migration is modulated by integrin signaling activation, suggesting that these adhesion molecules might be important target for therapeutic intervention in cardiovascular diseases. (C) 2010 Elsevier Ireland Ltd. All rights reserved.