ANTIPROLIFERATIVE ACT MUSCLE-CELLS AND RECEPTOR-BINDING OF HEPARIN-MIMICKING POLYAROMATIC ANIONIC COMPOUNDS
ANTIPROLIFERATIVE ACT MUSCLE-CELLS AND RECEPTOR-BINDING OF HEPARIN-MIMICKING POLYAROMATIC ANIONIC COMPOUNDS
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DOI：
10.1161/01.atv.14.12.1992
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发表时间：
1994-12-01
期刊：
影响因子：
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通讯作者：
VLODAVSKY, I
中科院分区：
文献类型：
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作者：
BENEZRA, M;BENSASSON, SA;VLODAVSKY, I
由凝血酶、碱性成纤维细胞生长因子或血清诱导的牛主动脉平滑肌细胞（SMC）的增殖被阴离子非硫酸化芳香族化合物抑制，这些化合物模拟肝素的许多作用。这些化合物包括金精三羧酸（ATA）和新合成的4-羟基苯氧基乙酸聚合物（化合物RG-13577）。碘化或C-14标记的化合物RG-13577以高度特异性和可饱和的方式与培养的SMC结合。结合数据的Scatchard分析显示，每个细胞估计存在1 × 10（7）个结合位点，表观解离常数为3 × 10（-6）mol/L。放射性标记的RG-13577的结合被相关芳香族阴离子化合物和载脂蛋白E有效竞争，但未被肝素、硫酸乙酰肝素、苏拉明或各种纯化生长因子和细胞外基质蛋白竞争。SMC结合I-125-RG-13577的受体交联显示，在不存在但不存在过量未标记化合物RG-13577的情况下，检测到单一种类的高M（r）（约280 kD）细胞表面受体。结合对受体水平的下调和恢复敏感，其方式与激素和生长因子受体相似。我们认为化合物RG-13577和相关化合物的抗增殖活性是通过与特异性生长抑制细胞表面受体结合而启动的。肝素模拟化合物可用于抑制与动脉粥样硬化和再狭窄相关的SMC增殖。
Proliferation of bovine aortic smooth muscle cells (SMCs) induced by thrombin, basic fibroblast growth factor, or serum is inhibited by anionic, nonsulfated aromatic compounds that mimic many of the effects of heparin. Among these compounds are aurintricarboxylic acid (ATA) and a newly synthesized polymer of 4-hydroxyphenoxy acetic acid (compound RG-13577). Iodinated- or C-14-labeled compound RG-13577 binds to cultured SMCs in a highly specific and saturable manner. Scatchard analysis of the binding data revealed the presence of an estimated 1x10(7) binding sites per cell with an apparent dissociation constant of 3x10(-6) mol/L. Binding of radiolabeled RG-13577 was efficiently competed for by related aromatic anionic compounds and by apolipoprotein E, but not by heparin, heparan sulfate, suramin, or various purified growth factors and extracellular matrix proteins. Receptor cross-linking of SMC-bound I-125-RG-13577 revealed a single species of high M(r) (approximate to 280 kD) cell surface receptors detected in the absence but not the presence of excess unlabeled compound RG-13577. Binding was susceptible to downregulation and restoration of receptor levels in a manner similar to that of hormone and growth factor receptors. We suggest that the antiproliferative activity of compound RG-13577 and related compounds is initiated by binding to specific growth-inhibiting cell surface receptors. Heparin-mimicking compounds may be applied to inhibit SMC proliferation associated with atherosclerosis and restenosis.