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Intrahepatic angiopoietin‐2 correlates with chronic hepatitis C progression and is induced in hepatitis C virus replicon systems
Author(s) -
HernándezBartolomé Ángel,
LópezRodríguez Rosario,
GarcíaBuey Luisa,
MartínVílchez Samuel,
RodríguezMuñoz Yolanda,
Borque María Jesús,
GonzálezMoreno Leticia,
RealMartínez Yolanda,
MendozaRidruejo Jorge,
MartínPérez Elena,
MorenoOtero Ricardo,
SanzCameno Paloma
Publication year - 2017
Publication title -
liver international
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.873
H-Index - 110
eISSN - 1478-3231
pISSN - 1478-3223
DOI - 10.1111/liv.13352
Subject(s) - hepatocellular carcinoma , angiogenesis , hepatitis c virus , biology , fibrosis , cirrhosis , immunology , hepatitis c , angiopoietin , angiopoietin receptor , cancer research , medicine , virus , vascular endothelial growth factor , vegf receptors
Abstract 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. Methods 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. Results 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. Conclusions 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.