Protecting effects of vasonatrin peptide against carbon tetrachloride-induced liver fibrosis.
In order to investigate the effects of vasonatrin peptide (VNP), a novel man-made natriuretic peptide, on liver fibrosis, mice received carbon tetrachloride (CCl(4)) injection for 12weeks and with or without VNP treatment during the last 6weeks. Hematoxylin-eosin (HE) staining and Sirius red staining were performed to evaluate the status of liver fibrosis. After treatment of VNP, DNA and collagen synthesis of cultured HSC-T6 hepatic stellate cells were assessed by [(3)H]-thymidine and [(3)H]-proline incorporation, respectively. Additionally, involved signaling pathway was identified by radioimmunoassay to detect the levels of intracellular cGMP and by mimicking experiments using 8-br-cGMP (a membrane-permeable cGMP analog). Also, blocking experiments 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. As a result, VNP markedly alleviated CCl(4)-induced liver fibrosis in mice. In vitro, HSC-T6 cells demonstrated a dose-dependent reduction of DNA and collagen synthesis in the presence VNP. In addition, VNP significantly increased the intracellular levels of cGMP. These effects of VNP were mimicked by 8-br-cGMP, although inhibited by HS-142-1 or KT-5823. Taken together, VNP ameliorates liver fibrosis by inhibiting collagen production from hepatic stellate cells via guanylyl cyclase-coupled NPR/cGMP/PKG pathway, indicating that VNP might be a new effective reagent in the treatment of liver fibrosis.
Chen
Bao-Ying
BY
Department of Radiology, Tangdu Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China.
Qu
Ping
P
Tie
Ru
R
Zhu
Miao-Zhang
MZ
Zhu
Xiao-Xing
XX
Yu
Jun
J
D000818:Animals; D009320:Atrial Natriuretic Factor / Q000494:pharmacology / Q000627:therapeutic use*; D002227:Carbazoles / Q000494:pharmacology; D002251:Carbon Tetrachloride / Q000633:toxicity*; D002460:Cell Line; D003094:Collagen / Q000378:metabolism; D006152:Cyclic GMP / Q000378:metabolism; D017869:Cyclic GMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D055166:Hepatic Stellate Cells / Q000187:drug effects* / Q000378:metabolism; D008103:Liver Cirrhosis / Q000139:chemically induced* / Q000188:drug therapy*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051381:Rats
D002227:Carbazoles; D047428:Protein Kinase Inhibitors; C073601:KT 5823; C068986:ventricular natriuretic peptide, eel; D009320:Atrial Natriuretic Factor; D003094:Collagen; D002251:Carbon Tetrachloride; D017869:Cyclic GMP-Dependent Protein Kinases; D006152:Cyclic GMP