期刊
CIRCULATION RESEARCH
卷 96, 期 2, 页码 172-179出版社
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/01.RES.0000154595.87608.db
关键词
platelet-derived growth factor; bFGF release; FGFR-1; ERK; Akt
资金
- NHLBI NIH HHS [HL-18645] Funding Source: Medline
We have shown that the G protein-coupled receptor (GPCR) agonists, thrombin and Factor Xa, stimulate smooth muscle cell (SMC) proliferation through transactivation of the EGF receptor ( EGFR) or the FGF receptor (FGFR), both of which are tyrosine kinase receptors. In the present study, we investigated whether platelet-derived growth factor ( PDGF), a tyrosine kinase receptor agonist, might transactivate another tyrosine kinase receptor to induce SMC proliferation. Because heparin inhibits PDGF-mediated proliferation in human SMCs, we investigated whether the heparin-binding growth factor basic fibroblast growth factor ( bFGF) and one of its receptors, FGFR-1, play a role in the response of human arterial SMCs to PDGF-BB. PDGF-BB induced the release of bFGF and sustained phosphorylation of FGFR-1 (30 minutes to 6 hours). A bFGF-neutralizing antibody inhibited PDGF-BB-mediated phosphorylation of FGFR-1, DNA synthesis, and cell proliferation. In the presence of bFGF antibody, PDGF-BB-induced early activation of ERK ( 0 to 60 minutes) was not affected, whereas late ERK activation ( 2 to 4 hours) was reduced. When FGFR-1 expression was suppressed using small interfering RNA ( siRNA), ERK activation was reduced at late, but not early, time points after PDGF-BB stimulation. Addition of bFGF antibody to cells treated with siRNA to FGFR-1 had no further effect on ERK activation. Our results provide support for a novel mechanism by which PDGF-BB induces the release of bFGF and activation of FGFR-1 followed by the sustained activation of ERK and proliferation of human SMCs.
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