Dihydroartemisinin Restricts Hepatic Stellate Cell Contraction via an FXR-S1PR2-dependent Mechanism
Dihydroartemisinin Restricts Hepatic Stellate Cell Contraction via an FXR-S1PR2-dependent Mechanism
复制标题
双氢青蒿素通过 FXR-S1PR2 依赖性机制限制肝星状细胞收缩
作者：
Xu W;Lu C;Zhang F;Shao J;Zheng S
肝星状细胞（hepatic stellate cells，HSC）在肝纤维化和门脉高压的发病机制中起着重要的促进作用。当HSC响应于肝损伤而被激活时，其特征在于具有许多变化，其中HSC收缩是门静脉高压症的最常见原因。已有研究表明，双氢青蒿素（DHA）通过诱导HSC凋亡而成为一种潜在的抗肝纤维化天然产物，但DHA在调节HSC收缩中的作用及其机制尚不清楚。最近的研究强调了法尼醇X受体（FXR）和1-磷酸鞘氨醇受体2（S1 PR 2）在控制细胞收缩性中的重要性。这项研究表明，DHA以剂量和时间依赖性方式强烈诱导LX-2细胞中FXR的mRNA和蛋白表达，并抑制HSC活化，这意味着DHA对HSC收缩的可能影响。凝胶收缩试验和肌动蛋白细胞骨架的荧光染色证实，DHA剂量依赖性地限制LX-2细胞中胶原晶格的收缩和肌动蛋白应力纤维的重组。DHA还降低了负责HSC收缩力的肌球蛋白轻链的磷酸化。此外，功能获得或丧失分析显示DHA抑制HSC收缩的FXR和S1 PR 2依赖性机制，DHA通过调节FXR活化降低S1 PR 2表达。随后的工作表明，抑制Ca 2+依赖性和Ca 2+敏化信号转导有助于DHA诱导的HSC松弛。总之，这些发现表明DHA可以通过调节FXR/S1 PR 2途径介导的Ca 2+依赖性和Ca 2+敏化信号来限制HSC收缩。我们的发现使DHA成为门静脉高压症的潜在候选者。© 2016 IUBMB Life 68（5）：376-387，2016
Hepatic stellate cells (HSCs) are universally acknowledged to play a stimulative role in the pathogenesis of hepatic fibrosis and portal hypertension. HSCs when activated in response to liver injury are characterized with many changes, with HSC contraction being the most common cause of portal hypertension. Previous studies have shown that dihydroartemisinine (DHA) is a potential antifibrotic natural product by inducing HSC apoptosis, whereas the role of DHA in regulating HSC contraction and the mechanisms involved remain a riddle. Recent studies have emphasized on the importance of farnesoid X receptor (FXR) and sphingosine‐1‐phosphate receptor 2 (S1PR2) in controlling cell contractility. This study showed that DHA strongly induced the mRNA and protein expression of FXR in LX‐2 cells in a dose‐ and time‐dependent manner and inhibited HSC activation, implying a conceivable impact of DHA on HSC contraction. The gel contraction assays and fluorescence staining of actin cytoskeleton verified that DHA dose‐dependently limited contraction of collagen lattices and reorganization of actin stress fibers in LX‐2 cells. DHA also decreased the phosphorylation of myosin light chain that is responsible for the contractile force of HSCs. Furthermore, gain‐ or loss‐of‐function analyses exhibited a FXR‐ and S1PR2‐dependent mechanism of inhibiting HSC contraction by DHA, and DHA decreased S1PR2 expression by modulating FXR activation. Subsequent work revealed that inhibition of both Ca2+‐dependent and Ca2+‐sensitization signaling transductions contributed to DHA‐induced HSC relaxation. In summary, these findings suggest that DHA could restrict HSC contraction through modulating FXR/S1PR2 pathway‐mediated Ca2+‐dependent and Ca2+‐sensitization signaling. Our discoveries make DHA a potential candidate for portal hypertension. © 2016 IUBMB Life 68(5):376–387, 2016