TNP-470 blockage of VEGF synthesis is dependent on MAPK/COX-2 signaling pathway in PDGF-BB-activated hepatic stellate cells.

Abstract:

:Angiogenesis is a key pathogenic event in hepatic fibrogenesis, which is mediated by activated hepatic stellate cells (HSCs). TNP-470 is a known anti-angiogenic agent in cancer, and in this study, we investigated the regulatory mechanisms of TNP-470 blockage of vascular endothelial growth factor (VEGF) synthesis in activated HSCs. Primary HSCs were isolated from rat liver, cultured in vitro, and activated with platelet-derived growth factor-BB (PDGF-BB). After treatment with TNP-470, Nimesulide, PD98059, SB203580 or SP600125, activated HSCs were analyzed by immunoblotting, quantitative RT-PCR, and ELISA for mitogen-activated protein kinase (MAPK) family [ERKs, JNK, and p38], cyclooxygenase-2 (COX-2), and VEGF levels. Phosphorylation of p44/42 MAPK, which was followed by increased expressions of COX-2 and VEGF, was observed in PDGF-BB-activated HSCs; these events could be ameliorated by addition with TNP-470 in time- and dose-dependent manners. TNP-470 also inhibited the secretion of VEGF from activated HSCs into culture supernatant. Furthermore, TNP-470 blockage of VEGF production in activated HSCs could be nullified by exogenous inoculation with prostaglandin E(2). In summary, our findings suggest that TNP-470 exhibits the observed anti-angiogenic properties in activated HSCs by targeting the COX-2/phospho-p44/42 MAPK pathway to inhibit VEGF production.

authors

Wang YQ,Luk JM,Chu AC,Ikeda K,Man K,Kaneda K,Fan ST

doi

10.1016/j.bbrc.2005.12.175

subject

Has Abstract

pub_date

2006-03-03 00:00:00

pages

239-44

issue

1

eissn

0006-291X

issn

1090-2104

pii

S0006-291X(05)02899-8

journal_volume

341

pub_type

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