title: Xuefuzhuyu decoction inhibition of angiogenesis attenuates liver fibrosis induced by CCl₄ in mice.
abstract: BACKGROUND
  Xuefuzhuyu decoction (XFZY) is a well-known traditional Chinese herbal formulation composed of 11 herbs. It is an effective treatment for cardiovascular and chronic liver diseases. The aim of the study is to investigate the role of XFZY on angiogensis in hepatic fibrogenesis, and identify the possible mechanism.
  
  
  METHODS
  Liver fibrosis was induced by intraperitoneal injection of Carbon tetrachloride (CCl₄) in C57BL/6 mice for 6 weeks. From week 4 to week 6, the CCl₄-injected mice were randomly divided into three groups, followed by oral administration of Sorafenib, XFZY and water for 3 weeks. Biochemical parameters, hydroxyproline (Hyp) content and histological changes of the liver were determined. The expressions of alpha smooth muscle actin (α-SMA), collagen I, CD31 and vascular endothelial grow factor (VEGF) were assessed by immunohistochemistry and western blot. The protein expressions of VEGFR-2, hypoxia inducing factor (HIF)-1α, asymmetric dimethylarginine (ADMA) and dimethylarginine hydrolase (DDAH) 1 were determined by western blot. The mRNA levels of α-SMA, VEGF and HIF-1α were measured by RT-PCR.
  
  
  RESULTS
  Both Sorafenib and XFZY improved biochemical parameters of the liver fibrosis mice. A significant reduction in Hyp content was found in the XFZY-treated mice as well as the Sorafenib-treated mice. Changes in histopathology showed that Sorafenib and XFZY decreased inflammatory and fibrotic stages of the liver in fibrosis mice. Compared to CCl4 model group, Sorafenib and XFZY decreased α-SMA, collagen I, CD31, VEGF, VEGFR-2, HIF-1α and ADMA, and increased the expression of DDAH1.
  
  
  CONCLUSIONS
  XFZY inhibits liver fibrosis not only through inhibiting collagen deposition but also through an antiangiogenic effect on the fibrotic liver. Moreover, the antiangiogenic mechanism of XFZY involves alleviating hypoxia and protecting liver sinusoidal endothelial cell function.
authors.affiliation: Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Institute of Liver Diseases, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
authors.forename: Ya-Ning
authors.initials: YN
authors.lastname: Zhou
authors.affiliation: Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Institute of Liver Diseases, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China; E-institute of Shanghai Municipal Education Commission, Shanghai 201203, China.
authors.forename: Ming-Yu
authors.initials: MY
authors.lastname: Sun
authors.affiliation: Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Institute of Liver Diseases, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
authors.forename: Yong-Ping
authors.initials: YP
authors.lastname: Mu
authors.affiliation: Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Institute of Liver Diseases, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
authors.forename: Tao
authors.initials: T
authors.lastname: Yang
authors.affiliation: Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
authors.forename: Bing-Bing
authors.initials: BB
authors.lastname: Ning
authors.affiliation: Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Institute of Liver Diseases, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
authors.forename: Shuang
authors.initials: S
authors.lastname: Ren
authors.affiliation: Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Institute of Liver Diseases, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
authors.forename: Jia-Mei
authors.initials: JM
authors.lastname: Chen
authors.affiliation: Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Institute of Liver Diseases, Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China; E-institute of Shanghai Municipal Education Commission, Shanghai 201203, China. Electronic address: liuliver@vip.sina.com.
authors.forename: Ping
authors.initials: P
authors.lastname: Liu
mesh_terms: D000199:Actins / Q000235:genetics / Q000378:metabolism; D000581:Amidohydrolases / Q000378:metabolism; D020533:Angiogenesis Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D002251:Carbon Tetrachloride; D024042:Collagen Type I / Q000378:metabolism; D004365:Drugs, Chinese Herbal / Q000494:pharmacology / Q000627:therapeutic use*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008103:Liver Cirrhosis / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008810:Mice, Inbred C57BL; D008517:Phytotherapy; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism
chemical_list: D000199:Actins; D020533:Angiogenesis Inhibitors; D024042:Collagen Type I; D004365:Drugs, Chinese Herbal; C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D042461:Vascular Endothelial Growth Factor A; C513826:Xue-Fu-Zhu-Yu decoction; C467480:vascular endothelial growth factor A, mouse; D002251:Carbon Tetrachloride; C000592875:Kdr protein, mouse; D040301:Vascular Endothelial Growth Factor Receptor-2; D000581:Amidohydrolases; C059999:dimethylargininase
keywords: Angiogenesis; Fibrosis; Xuefuzhuyu decoction