Role of hepatocyte NADPH Oxidase 4 in oxidative stress and DNA damage by genotype 1a hepatitis C virus
Hepatitis C virus (HCV) infection can lead to chronic infection resulting in severe liver diseases, including cirrhosis and hepatocellular carcinoma (HCC). Chronic hepatitis C (CHC) is characterized by ongoing inflammation and generation of reactive oxygen species (ROS) such as superoxide (O2.-) and hydrogen peroxide (H2O2). NADPH oxidase (Nox) enzymes produce ROS as their primary function and have been associated with oxidative stress in CHC. However, the precise role that Nox enzymes play in the pathogenesis of HCC is still unclear. We show that the structural core protein of genotype 1a HCV is sufficient to elevate Nox1 and 4 mRNA, protein expression, and enzyme activity and H2O2 levels in vitro. Human hepatocytes constitutively expressing core exhibited elevated Nox4 in the nucleus and increased DNA damage markers. Furthermore, the novel Nox-specific inhibitor VAS-2870 was capable of decreasing the core-associated increase in Nox enzyme activity. Altogether, these results highlight the importance of developing therapeutic agents targeting Nox enzymes for use as adjunct treatment of CHC to prevent carcinogenesis.