Inhibition of tyrosine kinase receptor Tie2 reverts HCV-induced hepatic stellate cell activation

• Published in: PloS one 2014-10, Vol.9 (10), p.e106958-e106958
• Main Authors: Martín-Vílchez, Samuel, Rodríguez-Muñoz, Yolanda, López-Rodríguez, Rosario, Hernández-Bartolomé, Borque-Iñurrita, María Jesús, Molina-Jiménez, Francisca, García-Buey, Luisa, Moreno-Otero, Ricardo, Sanz-Cameno, Paloma
• Format: Article
• Language: English
• Subjects: Actin; AKT protein; Analysis; Angiogenesis; Antibodies, Neutralizing - pharmacology; Biology and life sciences; Cell activation; Cell Line; Cell Movement - drug effects; Chronic infection; Collagen; Conditioning; Extracellular matrix; Fibrosis; Gene expression; Health aspects; Hepacivirus - physiology; Hepatic Stellate Cells - drug effects; Hepatic Stellate Cells - enzymology; Hepatic Stellate Cells - pathology; Hepatic Stellate Cells - virology; Hepatitis; Hepatitis C; Hepatitis C virus; Hepatitis C, Chronic - drug therapy; Hepatitis C, Chronic - enzymology; Hepatitis C, Chronic - pathology; Hepatocellular carcinoma; Hepatology; Humans; Infection; Inhibitors; Kinases; Ligands; Liver; Liver - pathology; Liver - virology; Liver diseases; MAP kinase; Medicine and health sciences; Microvasculature; Muscle proteins; Muscles; Neutralizing; Penicillin; Protein Kinase Inhibitors - pharmacology; Protein-tyrosine kinase receptors; Receptor, TIE-2 - analysis; Receptor, TIE-2 - antagonists & inhibitors; Receptors; Rodents; Signaling; Smooth muscle; Stellate cells; Therapeutic applications; Tyrosine; Vascular endothelial growth factor; Viruses
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0106958

Hepatitis C virus (HCV) infection is a major cause of chronic liver disease (CLD) and is frequently linked to intrahepatic microvascular disorders. Activation of hepatic stellate cells (HSC) is a central event in liver damage, due to their contribution to hepatic renewal and to the development of fibrosis and hepatocarcinoma. During the progression of CLDs, HSC attempt to restore injured tissue by stimulating repair processes, such as fibrosis and angiogenesis. Because HSC express the key vascular receptor Tie2, among other angiogenic receptors and mediators, we analyzed its involvement in the development of CLD. Tie2 expression was monitored in HSC cultures that were exposed to media from HCV-expressing cells (replicons). The effects of Tie2 blockade on HSC activation by either neutralizing antibody or specific signaling inhibitors were also examined. Media from HCV-replicons enhanced HSC activation and invasion and upregulated Tie2 expression. Notably, the blockade of Tie2 receptor (by a specific neutralizing antibody) or signaling (by selective AKT and MAPK inhibitors) significantly reduced alpha-smooth muscle actin (α-SMA) expression and the invasive potential of HCV-conditioned HSC. These findings ascribe a novel profibrogenic function to Tie2 receptor in the progression of chronic hepatitis C, highlighting the significance of its dysregulation in the evolution of CLDs and its potential as a novel therapeutic target.