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

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

Research output: Contribution to journalArticlepeer-review

35 Scopus citations

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 α-smooth muscle actin (α-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 α-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.

Original languageEnglish
Pages (from-to)209-221
Number of pages13
JournalLaboratory Investigation
Volume89
Issue number2
DOIs
StatePublished - Feb 2009

Keywords

  • Akt
  • Apoptosis
  • Cell cycle
  • Hepatic stellate cell
  • Liver fibrosis
  • PTK787/ZK22258

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