PTK787/ZK22258 attenuates stellate cell activation and hepatic fibrosis in vivo by inhibiting VEGF signaling

Lab Invest. 2009 Feb;89(2):209-21. doi: 10.1038/labinvest.2008.127. Epub 2008 Dec 29.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

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

Substances

  • 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