activation of protein serinethreonine phosphatase pp2cα efficiently prevents liver fibrosis激活的蛋白质serinethreonine磷酸酶pp2cα有效防止肝纤维化.pdfVIP

Activation of Protein Serine/Threonine Phosphatase PP2Ca Efficiently Prevents Liver Fibrosis 1. 1. 1 1 1 1 1,2 Lirui Wang , Xu Wang , Jing Chen , Zhengyi Yang , Liang Yu , Lihong Hu *, Xu Shen * 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 TGFb signaling pathway and uncontrolled cell proliferation of hepatic stellate cells (HSCs) play pivotal roles in liver fibrogenesis, while the protein serine/threonine phosphatase PP2Ca was reported to negatively regulate TGFb signaling pathway and cell cycle. Our study aimed to investigate the role of PP2Ca in liver fibrogenesis. Methodology/Principal Findings: The effects of PP2Ca 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 PP2Ca by overexpression or the new discovered small molecular activator NPLC0393 terminated TGFb-Smad3 and TGFb-p38 signaling pathways, induced cell cycle arrest in HSCs and decreased a-smooth muscle actin (a-SMA) expression, collagen deposition and hepatic hydroxyproline (HYP) level in CCl4- and BDL-induced mice. Conclusions/Significance: Our findings suggested that PP2Ca activation might be an attractive new st