The anti-hepatic fibrosis effects of dihydrotanshinone I are mediated by disrupting the yes-associated protein and transcriptional enhancer factor D2 complex and stimulating autophagy
The anti-hepatic fibrosis effects of dihydrotanshinone I are mediated by disrupting the yes-associated protein and transcriptional enhancer factor D2 complex and stimulating autophagy
复制标题
二氢丹参酮 I 的抗肝纤维化作用是通过破坏 yes 相关蛋白和转录增强因子 D2 复合物并刺激自噬介导的
DOI：
10.1111/bph.13766
复制
发表时间：
2017-05-01
影响因子：
7.3
通讯作者：
Shao, Rong-guang
中科院分区：
文献类型：
--
作者：
Ge, Maoxu;Liu, Hong;Shao, Rong-guang
背景与目的丹参酮I （hydrotanshinone I， DHI）是中药丹参的亲脂性成分，具有多种治疗作用。我们在体外和体内研究了DHI的抗纤维化作用及其潜在机制。实验方法胆管结扎（BDL）大鼠给予DHI （25 mg.kg(-1)）治疗。天（-1），i.p.)，共14天。进行血清生化和肝组织形态学分析。人肝星状细胞系LX-2作为肝纤维化体外模型。采用western blot和real-time PCR检测肝纤维化基因、yes-associated protein （YAP）下游基因和自噬标志物。在大鼠原代肝星状细胞（pHSCs）中进行了类似的分析。免疫荧光法测定自噬通量。关键结果在BDL大鼠中，DHI可减轻肝坏死、胆管增生和胶原积累，并降低与纤维化相关的基因Tgfb1、Mmp-2、Acta2和Col1a1的表达。DHI （1,5,10 mu mol.L-1）对LX-2细胞和大鼠pHSCs中COL1A1、TGF β 1和α - sma蛋白水平具有时间和剂量依赖性。此外，DHI阻断了YAP的核易位，从而抑制了YAP/TEAD2及其下游纤维化基因结缔组织生长因子、SOX4和survivin的相互作用。这刺激了自噬通量，加速了肝胶原蛋白的降解。结论与意义dhi通过抑制YAP和TEAD2复合物并刺激自噬，对BDL大鼠、LX-2细胞和大鼠phsc具有抗纤维化作用。这些发现表明，DHI可能是治疗肝纤维化的潜在疗法。
BACKGROUND AND PURPOSEDihydrotanshinone I (DHI), a lipophilic component of traditional Chinese medicine Salvia miltiorrhiza Bunge, has various therapeutic effects. We investigated the anti-fibrotic effect of DHI and its underlying mechanisms in vitro and in vivo.EXPERIMENTAL APPROACHRats subjected to bile duct ligation (BDL) were treated with DHI (25 mg.kg(-1).day(-1), i.p.) for 14 days. Serum biochemical and liver tissue morphological analyses were performed. The human hepatic stellate cell line LX-2 served as a liver fibrosis model in vitro. Liver fibrogenic genes, yes-associated protein (YAP) downstream genes and autophagy markers were examined using western blot and real-time PCR analyses. Similar analyses were done in rat primary hepatic stellate cells (pHSCs). Autophagy flux was assessed by immunofluorescence.KEY RESULTSIn BDL rats, DHI administration attenuated liver necrosis, bile duct proliferation and collagen accumulation and reduced the expression of genes associated with fibrogenesis, including Tgfb1, Mmp-2, Acta2 and Col1a1. DHI (1, 5, 10 mu mol.L-1) time-and dose-dependently suppressed the protein level of COL1A1, TGF beta 1 and alpha-SMA in LX-2 cells and rat pHSCs. Furthermore, DHI blocked the nuclear translocation of YAP, which inhibited the YAP/TEAD2 interaction and its downstream fibrogenic genes, connective tissue growth factor, SOX4 and survivin. This stimulated autophagic flux and accelerated the degradation of liver collagen.CONCLUSIONS AND IMPLICATIONSDHI exerts anti-fibrotic effects in BDL rats, LX-2 cells and rat pHSCs by inhibiting the YAP and TEAD2 complex and stimulating autophagy. These findings indicate that DHI may be a potential therapeutic for the treatment of liver fibrosis.