Sphingosine kinase/sphingosine 1-phosphate (S1P)/S1P receptor axis is involved in liver fibrosis-associated angiogenesis

被引：114

作者：

Yang, Le ^{[1
]}

Yue, Shi ^{[1
]}

Yang, Lin ^{[1
]}

Liu, Xin ^{[1
]}

Han, Zhen ^{[1
]}

Zhang, Yuanyuan ^{[1
]}

Li, Liying ^{[1
]}

机构：

[1] Capital Med Univ, Dept Cell Biol, Municipal Lab Liver Protect & Regulat Regenerat, Beijing 100069, Peoples R China

来源：

JOURNAL OF HEPATOLOGY | 2013年 / 59卷 / 01期

关键词：

Angiopoietin; 1; Vascular cell adhesion molecule-1; von Willebrand factor; Hepatic stellate cells; HEPATIC STELLATE CELLS; ENDOTHELIAL GROWTH-FACTOR; PROANGIOGENIC CYTOKINES; SPHINGOSINE-1-PHOSPHATE; ANGIOPOIETIN-1; FIBROGENESIS; ACTIVATION; INJURY;

D O I：

10.1016/j.jhep.2013.02.021

中图分类号：

R57 [消化系及腹部疾病];

学科分类号：

摘要：

Background & Aims: Sphingosine kinase (SphK)/sphingosine 1-phosphate (S1P)/S1P receptor (Si PR) axis is involved in multiple biological processes, including liver fibrosis. Angiogenesis is an important pathophysiological process closely associated with liver fibrosis; however, the functional role of SphK/S1P/S1PR in this process remains incompletely defined. Methods: Bile duct ligation or carbon tetrachloride was used to induce liver fibrosis in mice. Human fibrotic samples were obtained from livers of patients undergoing liver transplantation. S1P levels in the liver were examined by HPLC. Expression of angiogenic markers, including angiopoietin 1, CD31, vascular cell adhesion molecule-1, and von Willebrand factor, was characterized by immunofluorescence, real-time RT-PCR, and Western blot in the fibrotic liver and primary mouse hepatic stellate cells (HSCs). SphK inhibitor (SKI) or S1PR antagonists were administered intraperitoneally in mice. Results: SIP levels in the liver were closely correlated with mRNA expression of angiogenic markers. Ang1 is expressed in activated HSCs of the fibrotic liver and in primary HSCs. In HSCs, by using specific antagonists or siRNAs, we demonstrated S1P stimulation induced Ang1 expression via S1PR(1) and S1PR(3). In vivo, SIP reduction by SKI inhibited angiogenesis in fibrotic mice. Furthermore, S1PR(1/3) antagonist significantly blocked upregulation of angiogenic markers in the injured liver, and attenuated the extent of liver fibrosis, while S1PR(2) antagonist had no effect on angiogenesis, supporting the key role of S1PR(1) and S1PR(3) in angiogenesis underlying liver fibrosis process. Conclusions: SphK1/S1P/S1PR(1/3) axis plays a crucial role in the angiogenic process required for fibrosis development, which may represent an effective therapeutic strategy for liver fibrosis. (C) 2013 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

引用

页码：114 / 123

页数：10

共 32 条

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