File Download
There are no files associated with this item.
Links for fulltext
(May Require Subscription)
- Publisher Website: 10.1038/labinvest.2008.127
- Scopus: eid_2-s2.0-59049097181
- PMID: 19114984
- WOS: WOS:000262866700009
- Find via
Supplementary
-
Bookmarks:
- CiteULike: 1
- Citations:
- Appears in Collections:
Article: PTK787/ZK22258 attenuates stellate cell activation and hepatic fibrosis in vivo by inhibiting VEGF signaling
Title | PTK787/ZK22258 attenuates stellate cell activation and hepatic fibrosis in vivo by inhibiting VEGF signaling | ||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|
Authors | |||||||||||
Keywords | Akt Apoptosis Cell cycle Hepatic stellate cell Liver fibrosis PTK787/ZK22258 | ||||||||||
Issue Date | 2009 | ||||||||||
Publisher | Nature Publishing Group. The Journal's web site is located at http://www.nature.com/labinvest/ | ||||||||||
Citation | Laboratory Investigation, 2009, v. 89 n. 2, p. 209-221 How to Cite? | ||||||||||
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. © 2009 USCAP, Inc All rights reserved. | ||||||||||
Persistent Identifier | http://hdl.handle.net/10722/59961 | ||||||||||
ISSN | 2023 Impact Factor: 5.1 2023 SCImago Journal Rankings: 1.243 | ||||||||||
ISI Accession Number ID |
Funding Information: We thank Dr Jeremy Hughes ( Phagocyte Laboratory, MRC Center for Inflammation Research, University of Edinburgh, UK), Professor Mien-Chie Hung ( Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA) and Dr Nai-Sum Wong ( Department of Biochemistry, The University of Hong Kong) for their valuable advice and comments. Xueming Qian for technical assistant. This work was funded by Small Project Funding Programme of the University of Hong Kong, Shenzhen Bureau of Science, Technology and Information ( Shenzhen Key Laboratory Advancement Scheme). NIH Grant DK56621 and the Feld Fibrosis Fund, to SLF. | ||||||||||
References |
DC Field | Value | Language |
---|---|---|
dc.contributor.author | Liu, Y | en_HK |
dc.contributor.author | Lui, ELH | en_HK |
dc.contributor.author | Friedman, SL | en_HK |
dc.contributor.author | Li, L | en_HK |
dc.contributor.author | Ye, T | en_HK |
dc.contributor.author | Chen, Y | en_HK |
dc.contributor.author | Poon, RT | en_HK |
dc.contributor.author | Wo, J | en_HK |
dc.contributor.author | Kok, TW | en_HK |
dc.contributor.author | Fan, ST | en_HK |
dc.date.accessioned | 2010-05-31T04:00:57Z | - |
dc.date.available | 2010-05-31T04:00:57Z | - |
dc.date.issued | 2009 | en_HK |
dc.identifier.citation | Laboratory Investigation, 2009, v. 89 n. 2, p. 209-221 | en_HK |
dc.identifier.issn | 0023-6837 | en_HK |
dc.identifier.uri | http://hdl.handle.net/10722/59961 | - |
dc.description.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. © 2009 USCAP, Inc All rights reserved. | en_HK |
dc.language | eng | en_HK |
dc.publisher | Nature Publishing Group. The Journal's web site is located at http://www.nature.com/labinvest/ | en_HK |
dc.relation.ispartof | Laboratory Investigation | en_HK |
dc.subject | Akt | en_HK |
dc.subject | Apoptosis | en_HK |
dc.subject | Cell cycle | en_HK |
dc.subject | Hepatic stellate cell | en_HK |
dc.subject | Liver fibrosis | en_HK |
dc.subject | PTK787/ZK22258 | en_HK |
dc.title | PTK787/ZK22258 attenuates stellate cell activation and hepatic fibrosis in vivo by inhibiting VEGF signaling | en_HK |
dc.type | Article | en_HK |
dc.identifier.openurl | http://library.hku.hk:4550/resserv?sid=HKU:IR&issn=0023-6837&volume=89&issue=2&spage=209&epage=221&date=2009&atitle=PTK787/ZK22258+attenuates+stellate+cell+activation+and+hepatic+fibrosis+in+vivo+by+inhibiting+VEGF+signaling | en_HK |
dc.identifier.email | Poon, RT: poontp@hkucc.hku.hk | en_HK |
dc.identifier.email | Fan, ST: stfan@hku.hk | en_HK |
dc.identifier.authority | Poon, RT=rp00446 | en_HK |
dc.identifier.authority | Fan, ST=rp00355 | en_HK |
dc.description.nature | link_to_subscribed_fulltext | - |
dc.identifier.doi | 10.1038/labinvest.2008.127 | en_HK |
dc.identifier.pmid | 19114984 | - |
dc.identifier.scopus | eid_2-s2.0-59049097181 | en_HK |
dc.identifier.hkuros | 154349 | en_HK |
dc.relation.references | http://www.scopus.com/mlt/select.url?eid=2-s2.0-59049097181&selection=ref&src=s&origin=recordpage | en_HK |
dc.identifier.volume | 89 | en_HK |
dc.identifier.issue | 2 | en_HK |
dc.identifier.spage | 209 | en_HK |
dc.identifier.epage | 221 | en_HK |
dc.identifier.isi | WOS:000262866700009 | - |
dc.publisher.place | United Kingdom | en_HK |
dc.identifier.scopusauthorid | Liu, Y=14627533300 | en_HK |
dc.identifier.scopusauthorid | Lui, ELH=36865643400 | en_HK |
dc.identifier.scopusauthorid | Friedman, SL=35406698100 | en_HK |
dc.identifier.scopusauthorid | Li, L=26643123700 | en_HK |
dc.identifier.scopusauthorid | Ye, T=7102429442 | en_HK |
dc.identifier.scopusauthorid | Chen, Y=37095385900 | en_HK |
dc.identifier.scopusauthorid | Poon, RT=7103097223 | en_HK |
dc.identifier.scopusauthorid | Wo, J=7003466728 | en_HK |
dc.identifier.scopusauthorid | Kok, TW=36851058500 | en_HK |
dc.identifier.scopusauthorid | Fan, ST=7402678224 | en_HK |
dc.identifier.citeulike | 3837661 | - |
dc.identifier.issnl | 0023-6837 | - |