Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:4.2.2.7 (heparinase)
 1,270 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Previous work has demonstrated that aortic endothelial cells (EC) produce a heparin-like inhibitor of smooth muscle cell (SMC) growth when both cell types were cultured on plastic. We have now tested the influence of the extracellular matrix on this EC-SMC interaction. Specifically, we examined: 1) the role of different substrates (plastic, fibronectin, monomeric, and fibrillar collagens I and III, and EC-derived matrices) on the growth rate and population density of SMC; 2) the heparin-sensitivity of SMC on these diverse substrates; and 3) the effect of these same substrates on EC ability to secrete heparin-like and polypeptide inhibitors of SMC growth. SMC demonstrated a sixfold difference in sensitivity to heparin when grown on different substrates, with the following rank order: EGTA matrix greater than collagens = plastic = fibronectin greater than deoxycholic acid (DOC) matrix. Maximally, we found a 10-fold difference in the potency of the inhibitory activity secreted by EC grown on different substrates, with the following order: plastic = EGTA matrix greater than fibronectin greater than collagens = DOC matrix. Treatment of the conditioned mediums with heparinase and trypsin indicated that 58% to 76% of the inhibitory activity was due to heparin-like species, and 24% to 42% was due to protein(s). When EC cultured on EGTA matrix are compared to those pleated on DOC matrix, the potency of the heparin-like and peptide inhibitory activities increased 8- and 17-fold, respectively. Hypothetically, one would predict a 60-fold change in the potency of the antiproliferative effect if the contributions of substrate to EC production of inhibitors and SMC sensitivity were additive.(ABSTRACT TRUNCATED AT 250 WORDS)
Arteriosclerosis
PMID:Regulation of vascular smooth muscle cell growth by endothelial-synthesized extracellular matrices. 367 5

Heparan sulfate (HS) proteoglycans play a key role in cell proliferation induced by basic fibroblast growth factor (FGF-2) and other heparin-binding growth factors. To modulate the involvement of HS, we have used a synthetic, nonsulfated polyanionic aromatic compound (RG-13577) that mimics functional features of heparin/HS. FGF-2-stimulated proliferation of vascular endothelial cells was markedly inhibited in the presence of 5-10 microg/ml compound RG-13577 (poly-4-hydroxyphenoxy acetic acid; Mr approximately 5 kD). Direct interaction between RG-13577 and FGF-2 was demonstrated by the ability of the former to compete with heparin on binding to FGF-2. RG-13577 inhibited FGF-2 binding to soluble- and cell surface-FGF receptor 1 (FGFR1). Unlike heparin, RG-13577 alone failed to mediate dimerization of FGF-2. Moreover, it abrogated heparin-mediated dimerization of FGF-2 and FGFR1, as well as FGF-2 mitogenic activity in HS-deficient F32 lymphoid cells. The antiproliferative effect of compound RG-13577 was associated with abrogation of FGF-2-induced tyrosine phosphorylation of FGFR1 and of cytoplasmic proteins involved in FGF-2 signal transduction, such as p90 and mitogen-activated protein kinase. A more effective inhibition of tyrosine phosphorylation was obtained after removal of the cell surface HS by heparinase. In contrast, tyrosine phosphorylation of an approximately 200-kD protein was stimulated by RG-13577, but not by heparin or FGF-2. RG-13577 prevented microvessel outgrowth from rat aortic rings embedded in a collagen gel. Development of nontoxic polyanionic compounds may provide an effective strategy to inhibit FGF-2-induced cell proliferation associated with angiogenesis, arteriosclerosis, and restenosis.
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PMID:Modulation of fibroblast growth factor-2 receptor binding, dimerization, signaling, and angiogenic activity by a synthetic heparin-mimicking polyanionic compound. 912