Abstract
BackgroundPathological angiogenesis is involved in the development of hepatocellular carcinoma. In patients with chronic hepatitis C (CHC), the level of angiogenic factor angiopoietin (ANGP)-2 is reported to be increased in the blood, correlating with fibrosis. In this study, we aimed to clarify whether blood ANGP-2 is useful as a biomarker for liver angiogenesis and fibrosis in CHC patients and to further reveal the relationship between such pathology in a carbon tetrachloride (CCl4)-treated liver fibrosis mouse model.MethodsPlasma levels of ANGP-2, expression of a liver sinusoidal endothelial cell (LSEC) marker (CD31), collagen deposition (Sirius Red staining) in the liver, clinical fibrosis markers (Mac-2 binding protein glycosylation isomer, virtual touch quantification, and liver stiffness measurement), and liver function (albumin bilirubin score) were examined in CHC patients. To determine the effects of an anti-angiogenic agent on liver fibrosis in vivo, sorafenib was administered to the CCl4-treated mice (BALB/c male).ResultsThe plasma levels of ANGP-2 were increased in CHC patients compared to healthy volunteers and decreased by the eradication of hepatitis C with direct-acting antivirals. In addition, plasma ANGP-2 levels were correlated with CD31 expression, collagen deposition, clinical fibrosis markers, and liver function. Sorafenib inhibited liver angiogenesis and fibrosis in the CCl4-treated mice and was accompanied by decreased ANGP-2 expression in LSECs.ConclusionsANGP-2 may serve as a useful biomarker for liver angiogenesis and fibrosis in CHC patients. In addition, angiogenesis and fibrosis may be closely related.
Highlights
Pathological angiogenesis is involved in the development of hepatocellular carcinoma
To further elucidate the relationship between angiogenesis and fibrosis in vivo, we examined the impact of ANGP-2 on liver pathology using sorafenib in a carbon tetrachloride (CCl4)-induced liver fibrosis mouse model
ET-1 level was elevated in chronic hepatitis C (CHC) patients, but it did not change after hepatitis C virus (HCV) eradication (Fig. 1b)
Summary
Pathological angiogenesis is involved in the development of hepatocellular carcinoma. In patients with chronic hepatitis C (CHC), the level of angiogenic factor angiopoietin (ANGP)-2 is reported to be increased in the blood, correlating with fibrosis. Results: The plasma levels of ANGP-2 were increased in CHC patients compared to healthy volunteers and decreased by the eradication of hepatitis C with direct-acting antivirals. Serum ANGP-2 levels appear to be correlated with liver stiffness in CHC patients [14] and increase based on stage progression from chronic hepatitis to cirrhosis [15]. In CHC patients who later developed HCC, ANGP-2 liver expression levels were higher than in patients who did not develop HCC [17] These reports suggest that ANGP-2 is one of the crucial factors that link angiogenesis with fibrosis as a reflection of the risk potential for liver carcinogenesis
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