血管钠肽通过激活NPR／cGMP／PKG信号转导通路抑制肝纤维化  

Vasonatrin peptide ameliorates hepatic fibrosis via NPR/cGMP/PKG signal transduction pathway

作　　者：赵鸽[1] 狄首印[1] 翟蒙恩[1] 胡松[1] 林晓彬[1] 陈宝莹[1] 

机构地区：[1]西安交通大学医学院第一附属医院麻醉科,710061

出　　处：《中华肝胆外科杂志》2012年第3期196-199,共4页Chinese Journal of Hepatobiliary Surgery

基　　金：基金项目：国家新药创制重大科技专项研发基金（2009ZX09103671）

摘　　要：目的研究人工合成的新的钠尿肽-血管钠肽（vasonatrinpeptide，VNP）对肝纤维化的抑制作用及其信号转导通路。方法用四氯化碳处理小鼠12周，实验组在后6周使用VNP，对照组不使用VNP。对肝组织行伊红和苏丹红染色来评价肝纤维化水平。在体外实验，用梯度浓度的VNP处理HSC—T6细胞，分别采用[^3HI-胸苷和[^3H]脯氨酸掺人法检测细胞合成DNA和胶原的水平。用8-br—cGMP（一种可穿过细胞膜的cGMP类似物）模拟VNP。用HS142—1（一种钠尿肽受体阻断剂）、KT-5823（PKG阻滞剂）阻断VNP的作用通路。用放射免疫的方法检测胞内cGMP水平。结果VNP显著减轻四氯化碳诱导的小鼠肝纤维化。离体实验发现，经VNP处理的HSC-T6细胞，其DNA和胶原合成呈现VNP剂量依赖性减少；VNP显著增高了胞内的cGMP水平。VNP的这些效应可以被8-br-cGMP模拟，也可以被HS-1421或KT-5823阻断。结论VNP可通过激活NPR／cGMP／PKG信号传导通路减少肝星形细胞胶原的产生。VNP可能是一个新的有效的治疗肝纤维化的药物。Objective To investigate the effects and signal transduction pathway of vasonatrin peptide （VNP）, a novel man-made natriuretic peptide, on hepatic fibrosis. Methods Mice were injected with carbon tetraehloride （CC14） for 12 weeks, with or without VNP treatment in the last 6 weeks. HE staining and Sirius red staining were performed to evaluate the status of hepatic fibrosis. In vitro after treatment of VNP, and DNA and collagen synthesis of cultured HSC T6 hepatic stellate cells were assessed by [^3 H]-thymidine and [^3 H] proline incorporation, respectively. The signaling pathway involved was identified by radioimmunoassay to detect the levels of intracellular eGMP, and by mimicking experiments using 8-br-cGMP （a membrane-permeable cGMP analog）. Blocking experi ments were performed using HS-142-1, an antagonist of guanylyl cyclase-coupled natriuretic peptide receptor （NPR）, or KT-5823,the cGMP-dependent protein kinase （PKG） inhibitor. Results VNP markedly alleviated CC14-induced liver fibrosis in mice. In vitro, HSC-T6 cells demonstrated a dose- dependent reduction of DNA and collagen synthesis in the presence of VNP. In addition, VNP signifi cantly increased intracellular levels of cGMP. The effects of VNP were mimicked by 8-br-cGMP, but they were inhibited by HS-142-1, or KT-5823. Conclusion VNP ameliorated liver fibrosis by inhibiting collagen production from hepatic stellate ceils via guanylyl cyclase-coupled NPR/eGMP/PKG signal pathway, indicating that VNP might be a new effective agent in the treatment of liver fibrosis.

关 键 词：血管钠肽 肝纤维化 四氯化碳 

分 类 号：R575.2[医药卫生—消化系统]