Abrogation of apoptosis through PDGF-BB-induced sulfated glycosaminoglycan synthesis and secretion

被引:16
作者
Cartel, NJ
Post, M
机构
[1] Hosp Sick Children, Res Inst, Program Lung Biol, Toronto, ON M5G 1X8, Canada
[2] Hosp Sick Children, Dept Pediat, Toronto, ON M5G 1X8, Canada
[3] Univ Toronto, Dept Physiol, Toronto, ON, Canada
[4] Univ Toronto, Dept Lab Med & Pathobiol, Toronto, ON, Canada
关键词
platelet-derived growth factor;
D O I
10.1152/ajplung.00275.2004
中图分类号
Q4 [生理学];
学科分类号
071003 [生理学];
摘要
Platelet-derived growth factor (PDGF)-BB- stimulated glycosaminoglycan (GAG) synthesis/secretion in fetal lung fibroblasts is dependent on sequential activation of the PDGF beta-receptor, phosphatidylinositol 3-kinase (PI3K), the serine/threonine kinase Akt-1,2, and the GTPase Rab3D. Because the Akt pathway has been implicated in cell survival mechanisms, we investigated whether the pathway regulating GAG synthesis/secretion was antiapoptotic. PDGF-BB treatment protected fetal lung fibroblasts against serum starvation-induced apoptosis, whereas wortmannin, an inhibitor of PI3K, abrogated this protective effect. Transfection of constitutively active Akt into fetal lung fibroblasts also safeguarded the cells from apoptosis induced by serum starvation. To determine whether the antiapoptotic response was due, at least in part, to GAGs, we treated lung fibroblasts with beta-D-xyloside as well as with topically applied GAGs, specifically those produced by fetal lung fibroblasts. beta-D-xyloside increased GAG synthesis/secretion and diminished apoptosis. Application of sulfated GAGs, chondroitin sulfate, and heparan sulfate, but not nonsulfated hyaluronan, also resulted in diminished apoptosis. Moreover, topically applied sulfated GAGs increased Bcl-associated death promoter phosphorylation and diminished caspase-3 and - 7 cleavage, indicating an antiapototic response. These data are compatible with the PDGF-BB-GAG signaling pathway regulating programmed fibroblast death in the fetal lung.
引用
收藏
页码:L285 / L293
页数:9
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