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: Yuqing Liu, Eric Lik Hang Lui, Scott L Friedman, Lei Li, Tao Ye, Yongjun Chen, Ronnie T Poon, Jana Wo, Tsz Wai Kok, Sheung Tat Fan
• Journal: Laboratory investigation; a journal of technical methods and pathology (Lab Invest) Vol. 89 Issue 2 Pg. 209-21 (Feb 2009) ISSN: 1530-0307 [Electronic] United States
• PMID: 19114984 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Actins
• Biomarkers
• Collagen Type I
• Phthalazines
• Protein Kinase Inhibitors
• Pyridines
• RNA, Messenger
• Tissue Inhibitor of Metalloproteinase-1
• Vascular Endothelial Growth Factor A
• smooth muscle actin, rat
• vascular endothelial growth factor A, rat
• vatalanib
• Oncogene Protein v-akt

Topics

• Actins (metabolism)
• Animals
• Biomarkers (metabolism)
• Cell Proliferation (drug effects)
• Collagen Type I (genetics, metabolism)
• Cytoskeleton (drug effects)
• Disease Models, Animal
• Dose-Response Relationship, Drug
• Gene Expression (drug effects)
• Hepatic Stellate Cells (drug effects, metabolism)
• Liver Cirrhosis (metabolism, prevention & control)
• Male
• Mice
• Mice, Inbred BALB C
• Oncogene Protein v-akt (genetics, metabolism)
• Phthalazines (toxicity)
• Protein Kinase Inhibitors (toxicity)
• Pyridines (toxicity)
• RNA, Messenger (metabolism)
• Rats
• Signal Transduction (drug effects)
• Tissue Inhibitor of Metalloproteinase-1 (genetics, metabolism)
• Vascular Endothelial Growth Factor A (genetics, metabolism)