title: PTK787/ZK22258 attenuates stellate cell activation and hepatic fibrosis in vivo by inhibiting VEGF signaling.
abstract: Liver fibrosis due to hepatic stellate cell (HSC) activation represents a common response to chronic liver injury. PTK787/ZK222584 (PTK/ZK) is a pan-VEGFR tyrosine kinase inhibitor. The aim of this study was to examine the effect of PTK/ZK in liver fibrosis. In primary HSCs, PTK/ZK inhibited the expression of alpha-smooth muscle actin (alpha-SMA), collagen, tissue inhibitor of metalloproteinase-1 (TIMP-1), as well as cell proliferation, migration and actin filament formation. PTK/ZK-induced apoptosis of HSCs, which was correlated with increased caspase-3 activation and suppressed Bcl-2 expression. PTK/ZK also induced cell cycle arrest, accompanied by increasing the expression of p27(Kip1) and downregulation of cyclin D1 and cyclin E. PTK/ZK significantly inhibited vascular endothelial growth factor (VEGF) expression, as well as VEGF-simulated cell proliferation and phosphorylation of Akt in activated HSCs. In a murine fibrotic liver, PTK/ZK attenuated collagen deposition and alpha-SMA expression in carbon tetrachloride-induced fibrosis in both a 'prevention' and 'treatment' dosing scheme. These beneficial effects were associated with reduced phosphorylation of Akt and suppressed mRNA expression of procollagen-(I), TIMP-1, matrix metalloproteinase-9 and CD31. These findings provide novel insights into the potential value of blocking VEGF signaling by a small molecule tyrosine kinase inhibitor in treating hepatic fibrosis.
authors.affiliation: Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hong Kong, China. yuqing_liu@hotmail.com
authors.forename: Yuqing
authors.initials: Y
authors.lastname: Liu
authors.forename: Eric Lik Hang
authors.initials: EL
authors.lastname: Lui
authors.forename: Scott L
authors.initials: SL
authors.lastname: Friedman
authors.forename: Lei
authors.initials: L
authors.lastname: Li
authors.forename: Tao
authors.initials: T
authors.lastname: Ye
authors.forename: Yongjun
authors.initials: Y
authors.lastname: Chen
authors.forename: Ronnie T
authors.initials: RT
authors.lastname: Poon
authors.forename: Jana
authors.initials: J
authors.lastname: Wo
authors.forename: Tsz Wai
authors.initials: TW
authors.lastname: Kok
authors.forename: Sheung Tat
authors.initials: ST
authors.lastname: Fan
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D024042:Collagen Type I / Q000235:genetics / Q000378:metabolism; D003599:Cytoskeleton / Q000187:drug effects; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D015870:Gene Expression / Q000187:drug effects; D055166:Hepatic Stellate Cells / Q000187:drug effects* / Q000378:metabolism; D008103:Liver Cirrhosis / Q000378:metabolism / Q000517:prevention & control*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D051058:Oncogene Protein v-akt / Q000235:genetics / Q000378:metabolism; D010793:Phthalazines / Q000633:toxicity*; D047428:Protein Kinase Inhibitors / Q000633:toxicity*; D011725:Pyridines / Q000633:toxicity*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000235:genetics / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism*
chemical_list: D000199:Actins; D015415:Biomarkers; D024042:Collagen Type I; D051058:Oncogene Protein v-akt; D010793:Phthalazines; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D012333:RNA, Messenger; D019715:Tissue Inhibitor of Metalloproteinase-1; D042461:Vascular Endothelial Growth Factor A; C498862:Acta2 protein, rat; C467498:vascular endothelial growth factor A, rat; C404768:vatalanib