TNF-alpha-induced migration of vascular smooth muscle cells is MAPK dependent.
TNF-alpha-induced migration of vascular smooth muscle cells is MAPK dependent.
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发表时间：
1999
期刊：
影响因子：
8.3
通讯作者：
S. Goetze;X. Xi;Y. Kawano;H. Kawano;E. Fleck;W. Hsueh;R. Law
中科院分区：
文献类型：
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作者：
S. Goetze;X. Xi;Y. Kawano;H. Kawano;E. Fleck;W. Hsueh;R. Law
血管平滑肌细胞（VSMC）的迁移是新内膜形成和动脉粥样硬化的关键事件，可能与炎症细胞的积累和趋化细胞因子的释放有关。肿瘤坏死因子- α (tnf - α)诱导炎症细胞和成纤维细胞趋化，但对tnf - α在VSMC中的趋化信号传导知之甚少。本研究的目的是探讨tnf - α在VSMC迁移中的作用，并阐明介导这一作用的趋化信号通路。tnf - α (50 ~ 400 U/mL)诱导培养大鼠主动脉VSMC的迁移呈剂量依赖性。由于已知细胞外信号调节激酶1/2丝裂原活化蛋白激酶（MAPK）的激活在血小板衍生生长因子导向和血管紧张素ii导向的这些细胞迁移中是必需的，我们使用MAPK抑制剂PD98059来确定tnf - α的趋化信号是否也涉及MAPK途径。我们发现，PD98059显著抑制了tnf - α导向的迁移。tnf - α (100 U/mL)在刺激后10分钟瞬时激活MAPK，最大诱导作用在治疗后2小时恢复到基线水平。只观察到一个单峰的MAPK活性增加。PD98059还以浓度依赖的方式阻断tnf - α刺激的MAPK激活，这与它对tnf - α定向迁移的抑制一致。为了确定哪个tnf - α受体参与了tnf - α诱导的MAPK激活，使用了针对p55 tnf - α受体-1 （TNF-R1）和p75 tnf - α受体-2 （TNF-R2）的抗体。VSMC表达这两种受体，但tnf α诱导的MAPK激活仅被TNF-R1抗体抑制。TNF-R2抗体无作用。已知噻唑烷二酮可抑制脂肪组织中的tnf - α信号传导，并减弱VSMC中血小板衍生生长因子导向和血管紧张素ii导向的迁移。因此，我们研究了噻唑烷二酮类药物曲格列酮（TRO）和罗格列酮（RSG）对tnf α诱导的迁移的影响。TRO和RSG均抑制迁移，但均未减弱tnf α诱导的MAPK激活，表明它们的抗迁移活性在MAPK下游发挥作用。这些实验提供了第一个证据，证明MAPK的早期激活是tnf - α介导的信号转导导致VSMC迁移的关键事件。此外，胰岛素增敏剂TRO和RSG对tnf - α定向迁移的抑制强调了它们作为血管保护剂的潜力。
-Migration of vascular smooth muscle cells (VSMC) is a key event in neointimal formation and atherosclerosis that may be linked to the accumulation of inflammatory cells and release of chemotactic cytokines. Tumor necrosis factor-alpha (TNF-alpha) induces chemotaxis of inflammatory cells and fibroblasts, but little is known about chemotactic signaling by TNF-alpha in VSMC. The aim of this study was to investigate the role of TNF-alpha in VSMC migration and to elucidate the chemotactic signaling pathways mediating this action. TNF-alpha (50 to 400 U/mL) induced migration of cultured rat aortic VSMC in a dose-dependent manner. Because activation of the extracellular signal-regulated kinase 1/2 mitogen-activated protein kinase (MAPK) is known to be required in platelet-derived growth factor-directed and angiotensin II-directed migration of these cells, we used the MAPK-inhibitor PD98059 to determine if chemotactic signaling by TNF-alpha involves the MAPK pathway as well. We found that TNF-alpha-directed migration was substantially inhibited by PD98059. TNF-alpha (100 U/mL) transiently activated MAPK with a maximal induction 10 minutes after stimulation that returned to baseline levels by 2 hours after treatment. Only a single peak of increased MAPK activity was seen. PD98059 also blocked TNF-alpha-stimulated MAPK activation in a concentration-dependent manner, which is consistent with its inhibition of TNF-alpha-directed migration. To identify which TNF-alpha receptor is involved in TNF-alpha-induced MAPK activation, antibodies against the p55 TNF-alpha receptor-1 (TNF-R1) and the p75 TNF-alpha receptor-2 (TNF-R2) were used. VSMC express both receptors, but TNF-alpha-induced MAPK activation was inhibited only by the TNF-R1 antibody. The TNF-R2 antibody had no effect. Thiazolidinediones are known to inhibit TNF-alpha signaling in adipose tissue and attenuate platelet-derived growth factor-directed and angiotensin II-directed migration in VSMC. We therefore investigated the effects of the thiazolidinediones troglitazone (TRO) and rosiglitazone (RSG) on TNF-alpha-induced migration. Both TRO and RSG inhibited migration, but neither attenuated TNF-alpha-induced MAPK activation, indicating that their antimigration activity was exerted downstream of MAPK. These experiments provide the first evidence that early activation of MAPK is a crucial event in TNF-alpha-mediated signal transduction leading to VSMC migration. Moreover, inhibition of TNF-alpha-directed migration by the insulin sensitizers TRO and RSG underscores their potential as vasculoprotective agents.