PLoS ONE:激活PP2Cα可能成为治疗肝纤维化的新策略

2010-12-15 00:00 · Prima

12月6日,国际重要学术期刊PLoS ONE在线发表了中科院上海药物研究所研究论文Activation of Protein Serine/Threonine Phosphatase PP2Cα Efficiently Prevents Liver Fibrosis (Wang

12月6日,国际重要学术期刊PLoS ONE在线发表了中科院上海药物研究所研究论文Activation of Protein Serine/Threonine Phosphatase PP2Cα Efficiently Prevents Liver Fibrosis (Wang L., et al., Plos One, 2010, 5(12), e14230)。

该项研究由沈旭课题组和胡立宏课题组合作,博士生王丽蕊和王旭等共同完成。肝纤维化及其终极阶段肝硬化是世界性的重大公共卫生难题,在肝纤维化的发生发展过程中,肝星状细胞(HSCs)的激活起着关键性的作用。肝脏受到有害刺激后,静息的HSCs被激活,进而分泌大量的炎症因子和促纤维化因子等导致细胞外基质的过量积累。与此同时,分泌的这些细胞因子还能够刺激HSCs的增殖并抑制其凋亡,最终导致肝纤维化程度的加剧。

该研究发现,在HSCs中过表达丝苏氨酸磷酸酶PP2Cα或者用筛选获得的其小分子激动剂NPLC0393处理细胞不仅能够阻断TGFβ-Smad3和TGFβ-p38通路,而且能够显著抑制HSCs的增殖,并最终导致胞外基质的主要组分I型胶原的表达减少。此外,基于四氯化碳和胆管结扎诱导的肝纤维化小鼠模型研究均体现了NPLC0393这一有效的抗纤维化效果。

该项成果首次提出激活PP2Cα有可能成为治疗肝纤维化的新策略,而发现的来源于植物绞股蓝的PP2Cα天然小分子激动剂NPLC0393将成为抗纤维化药物研发的先导化合物。目前,研究人员已申请了相应的中国专利。

推荐原文出处:

PLoS ONE doi:10.1371/journal.pone.0014230

Activation of Protein Serine/Threonine Phosphatase PP2Cα Efficiently Prevents Liver Fibrosis

Lirui Wang1#, Xu Wang1#, Jing Chen1, Zhengyi Yang1, Liang Yu1, Lihong Hu1*, Xu Shen1,2*

1 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China, 2 E-Institutes of Shanghai Municipal Education Commission, Shanghai Jiaotong University School of Medicine, Shanghai, China

Abstract

Background

Over-activation of TGFβ signaling pathway and uncontrolled cell proliferation of hepatic stellate cells (HSCs) play pivotal roles in liver fibrogenesis, while the protein serine/threonine phosphatase PP2Cα was reported to negatively regulate TGFβ signaling pathway and cell cycle. Our study aimed to investigate the role of PP2Cα in liver fibrogenesis.

Methodology/Principal Findings

The effects of PP2Cα activation on liver fibrosis were investigated in human HSCs and primary rat HSCs in vitro using western blotting, real-time PCR, nuclear translocation, cell viability and cell cycle analyses. The antifibrogenic effects in carbon tetrachloride (CCl4)- and bile duct ligation (BDL)-induced mice in vivo were assessed using biochemical, histological and immunohistochemical analyses. The results demonstrated that activation of PP2Cα by overexpression or the new discovered small molecular activator NPLC0393 terminated TGFβ-Smad3 and TGFβ-p38 signaling pathways, induced cell cycle arrest in HSCs and decreased α-smooth muscle actin (α-SMA) expression, collagen deposition and hepatic hydroxyproline (HYP) level in CCl4- and BDL-induced mice.

Conclusions/Significance

Our findings suggested that PP2Cα activation might be an attractive new strategy for treating liver fibrosis while the small molecular activator NPLC0393 might represent a lead compound for antifibrogenic drug development. Moreover, our study might provide the first evidence for the role of PP2C family members in the fibrotic disease.

关键词: