Adenoviral CCN 3/ NOV gene transfer fails to mitigate liver fibrosis in an experimental bile duct ligation model because of hepatocyte apoptosis

AbstractBackground and Aims CCN3/NOV, a matricellular protein of the CYR61‐CTGF‐NOV (CCN) family, comprises six secreted proteins that associate specifically with the extracellular matrix. CCN proteins lack specific high‐affinity receptors; instead, they regulate crucial biological processes, such as fibrosis, by signalling via integrins and proteoglycans. Recent studies have linked overexpression of CCN3/NOV to mitigate kidney fibrosis. This study aims to investigate CCN3/NOV overexpression in liver fibrogenesis in vivo.MethodsThe biological efficacy of adenoviral expressed CCN3/NOV directed under transcriptional control of the constitutively active Cytomegalovirus promoter (Ad‐NOV) was analysed in a bile duct ligation model and in cultured primary hepatocytes.Results and ConclusionsEven though Ad‐NOV gene transfer in a 3‐week bile duct ligation mouse model showed the expected high levels of CCN3/NOV in both mRNA and protein, it failed to reduce liver fibrogenesis, but instead enhanced hepatocyte apoptosis. Furthermore, overexpressed CCN3/NOV in cultured primary hepatocytes resulted in decreased levels of CCN2/CTGF, the profibrotic marker protein in liver fibrosis. Both Ad‐NOV and Ad‐CTGF induced reactive oxygen species production, enhanced p38 and JNK activation. Therefore, we conclude that CCN3/NOV overexpression in vivo is insufficient to mitigate liver fibrogenesis because of the induction of hepatocyte injury and apoptosis.