Xuefuzhuyu decoction inhibition of angiogenesis attenuates liver fibrosis induced by CCl4 in mice
Xuefuzhuyu decoction inhibition of angiogenesis attenuates liver fibrosis induced by CCl4 in mice
复制标题
血府逐瘀汤抑制血管生成减轻四氯化碳诱导的小鼠肝纤维化
DOI：
10.1016/j.jep.2014.03.019
复制
发表时间：
2014-05-14
影响因子：
5.4
通讯作者：
Liu, Ping
中科院分区：
文献类型：
--
作者：
Zhou, Ya-Ning;Sun, Ming-Yu;Liu, Ping
民族药理学相关性：血府逐瘀汤（XFZY）是由11种草药组成的著名传统中药制剂。它是心血管和慢性肝病的有效治疗方法。本研究的目的是探讨XFZY在肝纤维化形成中对血管生成的作用，并探讨其可能的机制。材料与方法：CCl 4腹腔注射诱导C57 BL/6小鼠肝纤维化6周。从第4周至第6周，将注射CCl 4的小鼠随机分为三组，随后口服施用索拉非尼、XFZY和水3周。测定肝脏生化指标、羟脯氨酸（Hyp）含量及组织学变化。采用免疫组化和western blot检测α-平滑肌肌动蛋白（α-SMA）、I型胶原、CD 31和血管内皮生长因子（VEGF）的表达。Western blot检测VEGFR-2、缺氧诱导因子（HIF）-1 α、不对称二甲基精氨酸（ADMA）和二甲基精氨酸水解酶（DDAH）1蛋白表达。结果：索拉非尼和XFZY均能改善肝纤维化小鼠的生化指标。在XFZY治疗的小鼠和索拉非尼治疗的小鼠中发现Hyp含量显着减少。组织病理学变化显示索拉非尼和XFZY降低了纤维化小鼠肝脏的炎症和纤维化阶段。与CCI 4模型组相比，索拉非尼和XFZY均能降低α-SMA、I型胶原、CD 31、VEGF、VEGFR-2、HIF-1 α和ADMA的表达，增加DDAH 1的表达。此外，XFZY的抗血管生成机制涉及减轻缺氧和保护肝窦内皮细胞功能。(C)2014爱思唯尔爱尔兰有限公司版权所有。
Ethnopharmacological relevance: 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.Material and methods: Liver fibrosis was induced by intraperitoneal injection of Carbon tetrachloride (CCI4) in C57BL/6 mice for 6 weeks. From week 4 to week 6, the CCI4-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 (alpha-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)-1 alpha, asymmetric dimethylarginine (ADMA) and dimethylarginine hydrolase (DDAH) 1 were determined by western blot. The mRNA levels of a-SMA, VEGF and HIF-1 alpha 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 CCI4 model group, Sorafenib and XFZY decreased a-SMA, collagen I, CD31, VEGF, VEGFR-2, HIF-l alpha and ADMA, and increased the expression of DDAHl.Conclusion: 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. (C) 2014 Elsevier Ireland Ltd. All rights reserved.