Liver Unit, Instituto Investigación Sanitaria Princesa, IIS-IP, Madrid, Spain.
CIBERehd, Instituto de Salud Carlos III, ISCIII, Madrid, Spain.
Liver Int. 2017 Aug;37(8):1148-1156. doi: 10.1111/liv.13352. Epub 2017 Feb 6.
BACKGROUND & AIMS: Chronic hepatitis C (CHC) is a major cause of cirrhosis and hepatocellular carcinoma and angiogenesis is closely related to the pathogenesis and progression of different chronic liver diseases (CLD). Thus, the intrahepatic expression of angiopoietins 1 and 2 (Ang1 and Ang2), as relevant mediators of pathological angiogenesis in several CLD, was investigated. In addition, the differential influence of structural and non-structural genomic regions of HCV on the expression of angiopoietins and the possible signalling involved were studied.
Ang1 and Ang2 expression was evaluated by western blotting and enzyme-linked immunosorbent assay (ELISA) in liver homogenates of CHC patients (n=47) and uninfected subjects (n=8). Their association with disease progression (according to METAVIR classification) was assessed by Spearman's correlation. Statistical differences among the expression of angiopoietins at different CHC stages were calculated by Mann-Whitney U-test. Finally, the in vitro expression of Angiopoietins in HCV replicons (complete or non-structural subgenomic) and the main signalling pathways involved were also examined.
Ang2 levels were significantly higher in the liver of CHC patients compared to controls and significantly correlated with inflammation and fibrosis. Accordingly, an increased expression of Ang2 was found in all HCV replicons tested. Interestingly, the inhibition of MEK and PI3K signalling pathways exerted differential effects on Ang2 expression concerning to the genomic region of HCV.
Hepatitis C virus induces Ang2 expression in hepatocytes through different signalling routes which may lead to the disregulation of vascular homeostasis in the liver. Thus, pharmacologic intervention on Ang2 signalling might constitute an important therapeutic tool.
慢性丙型肝炎（CHC）是肝硬化和肝细胞癌的主要病因，血管生成与不同慢性肝病（CLD）的发病机制和进展密切相关。因此，研究了血管生成素 1 和 2（Ang1 和 Ang2）在几种 CLD 中的病理性血管生成中的相关介质的肝内表达。此外，还研究了 HCV 的结构和非结构基因组区域对血管生成素表达的差异影响以及可能涉及的信号通路。
通过Western blot 和酶联免疫吸附试验（ELISA）评估 CHC 患者（n=47）和未感染患者（n=8）肝组织匀浆中 Ang1 和 Ang2 的表达。通过Spearman 相关性评估其与疾病进展（根据 METAVIR 分类）的相关性。通过 Mann-Whitney U 检验计算不同 CHC 阶段血管生成素表达的统计学差异。最后，还研究了 HCV 复制子（完整或非结构亚基因组）和涉及的主要信号通路中 Angiopoietins 的体外表达。
与对照组相比，CHC 患者的 Ang2 水平显着升高，并且与炎症和纤维化显着相关。相应地，在所有测试的 HCV 复制子中均发现 Ang2 表达增加。有趣的是，MEK 和 PI3K 信号通路的抑制对 HCV 基因组区域的 Ang2 表达产生了不同的影响。
丙型肝炎病毒通过不同的信号通路诱导肝细胞中 Ang2 的表达，这可能导致肝脏血管稳态失调。因此，对 Ang2 信号通路的药物干预可能是一种重要的治疗工具。
