Upregulated expression of hypoxia reactive genes in peripheral blood mononuclear cells from chronic liver disease patients

Abstract

Liver fibrosis induces intrahepatic microcirculation disorder and hypoxic stress. Hypoxic stress has the potential for an increase in the possibility of more liver fibrosis and carcinogenesis. Liver biopsy is a standard method that evaluates of intrahepatic hypoxia, however, is invasive and has a risk of bleeding as a complication. Here, we investigated the hypoxia reactive gene expressions in peripheral blood mononuclear cells (PBMC) from chronic liver disease patients to evaluate intrahepatic hypoxia in a non-invasive manner. The subjects enrolled for this study were composed of 20 healthy volunteers (HV) and 48 patients with chronic liver disease (CLD). CLD patients contained 24 patients with chronic hepatitis（CH）and 24 patients with liver cirrhosis (LC). PBMC were isolated from heparinized peripheral blood samples. We measured the transcriptional expression of hypoxia reactive genes and inflammatory cytokines by quantitative RT-PCR. mRNA expression of adrenomedullin (AM), vascular endothelial growth factor A (VEGFA) superoxide dismutase (SOD), glutathione peroxidase (GPx) (p < 0.05), Interleukin-6 (IL-6), transforming growth factor-beta (TGF-β) and heme oxygenase-1 (HO-1) in CLD group were significantly higher than HV. AM mRNA expression is correlated with serum lactate dehydrogenase (LDH), serum albumin (Alb), IL6, and SOD mRNA expression. The hypoxia reactive gene expression in PBMCs from CLD patients was more upregulated than HV. Especially, angiogenic genes were notably upregulated and correlated with liver fibrosis. Here, we suggest that mRNA expression of AM in PBMCs could be the biomarker of intrahepatic hypoxia.