Inhibition of YAP signaling contributes to senescence of hepatic stellate cells induced by tetramethylpyrazine
Inhibition of YAP signaling contributes to senescence of hepatic stellate cells induced by tetramethylpyrazine
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抑制 YAP 信号传导导致四甲基吡嗪诱导的肝星状细胞衰老
DOI：
10.1016/j.ejps.2016.10.002
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发表时间：
2017-01-01
影响因子：
4.6
通讯作者：
Zheng, Shizhong
中科院分区：
文献类型：
--
作者：
Jin, Huanhuan;Lian, Naqi;Zheng, Shizhong
越来越多的证据表明，肝星状细胞（HSC）是肝纤维化发展的中心介质和主要效应器。众所周知，细胞增殖和凋亡的调节是阻断HSC活化的潜在策略。近年来，多项研究表明诱导HSC衰老可以预防和治疗肝纤维化。在我们之前的工作中，我们已经证明天然产物四甲基吡嗪（TMP）可以抑制HSC的活化并改善肝纤维化。本研究的目的是确定 TMP 在调节激活的 HSC 衰老中的新作用并阐明其潜在机制。在这项研究中，我们的数据表明TMP可以在体内和体外促进HSC衰老。此外，TMP 影响细胞周期和端粒酶活性。我们进一步证明，P53 siRNA 或 P53 药理学抑制剂 PFT 可以在体外消除 TMP 诱导的 HSC 衰老。同时，在体内也获得了类似的结果。进一步的研究表明，TMP 通过 YAP 抑制依赖性机制促进 P53 的表达。此外，沉默 YAP 增强了 TMP 对活化 HSC 衰老的诱导。总的来说，我们的结果表明，TMP 通过诱导衰老来抑制 HSC 的活化，对肝纤维化的治疗具有治疗意义。 (C) 2016 Elsevier B.V. 保留所有权利。
Accumulating evidence indicates that hepatic stellate cells (HSCs) are the central mediators and major effectors in the development of hepatic fibrosis. It iswell-known that regulation of cell proliferation and apoptosis are potential strategies to block the activation of HSCs. Recently, several studies have revealed that induction of HSC senescence could prevent and cure the liver fibrosis. In our previous work, we have demonstrated that the natural product tetramethylpyrazine (TMP) could inhibit the activation of HSCs and ameliorate hepatic fibrosis. The aim of this study was to identify a new role of TMP in the regulation of activated HSC senescence and to elucidate the underlying mechanisms. In this study, our data showed that TMP could promote HSC senescence in vivo and in vitro. Moreover, TMP affected the cell cycle and telomerase activity. We further demonstrated that P53 siRNA or P53 pharmacological inhibitor PFT-aabrogated the TMP-induced HSC senescence in vitro. Meanwhile, similar results were obtained in vivo. Further studies indicated that TMP promoted the expression of P53 through a YAP inhibition-dependent mechanism. Moreover, silencing YAP enhanced TMP induction of activated HSC senescence. Collectively, our results suggested that TMP inhibited the activation of HSCs by inducing senescence and had therapeutic implication for the treatment of liver fibrosis. (C) 2016 Elsevier B.V. All rights reserved.