Schisandrin B suppresses TGFβ1-induced stress fiber formation by inhibiting myosin light chain phosphorylation
Schisandrin B suppresses TGFβ1-induced stress fiber formation by inhibiting myosin light chain phosphorylation
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DOI：
10.1016/j.jep.2014.01.024
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发表时间：
2014-03-14
影响因子：
5.4
通讯作者：
Jeon, Ju-Hong
中科院分区：
文献类型：
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作者：
Chun, Jung Nyeo;Kim, Sang-Yeob;Jeon, Ju-Hong
民族药理学相关性：五味子提取物（SCE）已被用作治疗血管疾病的传统东方药物。然而，SCE对血管纤维化的药理作用和机制仍不甚清楚。转化生长因子β 1 （TGF β 1）介导的细胞变化与血管纤维化疾病的发病密切相关。特别是TGF β 1诱导肌动蛋白应激纤维的形成，这是血管平滑肌细胞（VSMC）在血管损伤后迁移的重要机制。在本研究中，我们研究了SCE及其有效成分对TGF β 1诱导的A7r5 VSMCs中应力纤维组装的影响。材料和方法：为了研究SCE及其成分对TGF β 1处理的VSMCs的药理作用，我们采用了共聚焦显微镜、荧光共振能量转移、western blotting、放射酶分析等分子和细胞生物学技术。结果：我们发现SCE抑制TGF β 1诱导的应激纤维形成和细胞迁移。五味子素B （Schisandrin B, SchB）在SCE活性成分中作用最显著。SchB降低了TGF β 1介导的肌球蛋白轻链磷酸化，且这种作用不依赖于RhoA/ rho相关激酶途径。荧光共振能量转移和放射酶测定证实，SchB抑制肌球蛋白轻链激酶活性。我们还发现，SchB通过抑制Smad信号传导，降低TGF β 1介导的α -平滑肌肌动蛋白的诱导。结论：本研究表明SCE及其有效成分SchB在分子水平上抑制TGF β 1诱导的应激纤维形成。因此，我们的发现可能有助于未来的研究开发多靶向治疗策略，以减轻VSMC迁移和血管纤维化。2014爱思唯尔爱尔兰有限公司版权所有。
Ethnopharmacological relevance: Schisandra chinensis fruit extract (SCE) has been used as a traditional oriental medicine for treating vascular diseases. However, the pharmacologic effects and mechanisms of SCE on vascular fibrosis are still largely unknown. Transforming growth factor beta 1 (TGF beta 1)-mediated cellular changes are closely associated with the pathogenesis of vascular fibrotic diseases. Particularly, TGF beta 1 induces actin stress fiber formation that is a crucial mechanism underlying vascular smooth muscle cell (VSMC) migration in response to vascular injury. In this study, we investigated the effect of SCE and its active ingredients on TGF beta 1-induced stress fiber assembly in A7r5 VSMCs.Materials and methods: To investigate pharmacological actions of SCE and its ingredients on TGF beta 1-treated VSMCs, we have employed molecular and cell biological technologies, such as confocal microscopy, fluorescence resonance energy transfer, western blotting, and radiometric enzyme analyses.Results: We found that SCE inhibited TGF beta 1-induced stress fiber formation and cell migration. Schisandrin B (SchB) showed the most prominent effect among the active ingredients of SCE tested. SchB reduced TGF beta 1-mediated phosphorylation of myosin light chain, and this effect was independent of RhoA/Rho-associated kinase pathway. Fluorescence resonance energy transfer and radiometric enzyme assays confirmed that SchB inhibited myosin light chain kinase activity. We also showed that SchB decreased TGF beta 1-mediated induction of alpha-smooth muscle actin by inhibiting Smad signaling.Conclusions: The present study demonstrates that SCE and its active ingredient SchB suppressed TGF beta 1-induced stress fiber formation at the molecular level. Therefore, our findings may help future investigations to develop multi-targeted therapeutic strategies that attenuate VSMC migration and vascular fibrosis. (C) 2014 Elsevier Ireland Ltd. All rights reserved.