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

TitlePTK787/ZK22258 attenuates stellate cell activation and hepatic fibrosis in vivo by inhibiting VEGF signaling
Authors
KeywordsAkt
Apoptosis
Cell cycle
Hepatic stellate cell
Liver fibrosis
PTK787/ZK22258
Issue Date2009
PublisherNature 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?
AbstractLiver 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 Identifierhttp://hdl.handle.net/10722/59961
ISSN
2015 Impact Factor: 4.202
2015 SCImago Journal Rankings: 2.133
ISI Accession Number ID
Funding AgencyGrant Number
University of Hong Kong
Shenzhen Bureau of Science, Technology and Information
Shenzhen Key Laboratory Advancement Scheme
NIHDK56621
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 FieldValueLanguage
dc.contributor.authorLiu, Yen_HK
dc.contributor.authorLui, ELHen_HK
dc.contributor.authorFriedman, SLen_HK
dc.contributor.authorLi, Len_HK
dc.contributor.authorYe, Ten_HK
dc.contributor.authorChen, Yen_HK
dc.contributor.authorPoon, RTen_HK
dc.contributor.authorWo, Jen_HK
dc.contributor.authorKok, TWen_HK
dc.contributor.authorFan, STen_HK
dc.date.accessioned2010-05-31T04:00:57Z-
dc.date.available2010-05-31T04:00:57Z-
dc.date.issued2009en_HK
dc.identifier.citationLaboratory Investigation, 2009, v. 89 n. 2, p. 209-221en_HK
dc.identifier.issn0023-6837en_HK
dc.identifier.urihttp://hdl.handle.net/10722/59961-
dc.description.abstractLiver 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.languageengen_HK
dc.publisherNature Publishing Group. The Journal's web site is located at http://www.nature.com/labinvest/en_HK
dc.relation.ispartofLaboratory Investigationen_HK
dc.subjectAkten_HK
dc.subjectApoptosisen_HK
dc.subjectCell cycleen_HK
dc.subjectHepatic stellate cellen_HK
dc.subjectLiver fibrosisen_HK
dc.subjectPTK787/ZK22258en_HK
dc.titlePTK787/ZK22258 attenuates stellate cell activation and hepatic fibrosis in vivo by inhibiting VEGF signalingen_HK
dc.typeArticleen_HK
dc.identifier.openurlhttp://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+signalingen_HK
dc.identifier.emailPoon, RT: poontp@hkucc.hku.hken_HK
dc.identifier.emailFan, ST: stfan@hku.hken_HK
dc.identifier.authorityPoon, RT=rp00446en_HK
dc.identifier.authorityFan, ST=rp00355en_HK
dc.description.naturelink_to_subscribed_fulltext-
dc.identifier.doi10.1038/labinvest.2008.127en_HK
dc.identifier.pmid19114984-
dc.identifier.scopuseid_2-s2.0-59049097181en_HK
dc.identifier.hkuros154349en_HK
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-59049097181&selection=ref&src=s&origin=recordpageen_HK
dc.identifier.volume89en_HK
dc.identifier.issue2en_HK
dc.identifier.spage209en_HK
dc.identifier.epage221en_HK
dc.identifier.isiWOS:000262866700009-
dc.publisher.placeUnited Kingdomen_HK
dc.identifier.scopusauthoridLiu, Y=14627533300en_HK
dc.identifier.scopusauthoridLui, ELH=36865643400en_HK
dc.identifier.scopusauthoridFriedman, SL=35406698100en_HK
dc.identifier.scopusauthoridLi, L=26643123700en_HK
dc.identifier.scopusauthoridYe, T=7102429442en_HK
dc.identifier.scopusauthoridChen, Y=37095385900en_HK
dc.identifier.scopusauthoridPoon, RT=7103097223en_HK
dc.identifier.scopusauthoridWo, J=7003466728en_HK
dc.identifier.scopusauthoridKok, TW=36851058500en_HK
dc.identifier.scopusauthoridFan, ST=7402678224en_HK
dc.identifier.citeulike3837661-

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