Heparin modulates integrin-mediated cellular adhesion:: Specificity of interactions with α and β integrin subunits
Heparin modulates integrin-mediated cellular adhesion:: Specificity of interactions with α and β integrin subunits
复制标题
DOI：
10.1080/cac.10.2.59.67
复制
发表时间：
2003-03-01
影响因子：
--
通讯作者：
Sobel, M
中科院分区：
文献类型：
--
作者：
Da Silva, MS;Horton, JA;Sobel, M
众所周知，肝素可以影响血管细胞的生长、增殖和迁移，但确切的机制尚不清楚。我们以前证明了普通肝素(UH)与血小板整合素α(IIb)β(3)结合，并增强配体结合。为了帮助确定肝素-整合素相互作用的特异性和部位(S)，我们使用了红白血病K562细胞株，并通过转染表达了特定的整合素(α(V)β(3)，α(V)β(5)和α(IIb)β(3))。通过比较K562细胞表达一个共同的α亚基(Kalpha(V)beta(3)，Kalpha(V)beta(5))和表达一个共同的beta亚基的细胞(Kalpha(V)beta(3)，Kalpha(IIb)beta(3))，我们观察到肝素差异化地调节整合素介导的与Vitronectin的黏附。UH0.5-7.5µg/ml可持续增强表达β(3)的细胞(Kalpha(V)beta(3)，Kalpha(IIb)beta(3))的粘附性。相反，0.5-7.5mug/ml的UH可抑制Kalpha(V)β(5)的黏附。使用整合素阻断抗体、适当的对照配体和未转基因的天然K562细胞的实验表明，肝素的作用是由研究中的特定整合素介导的。肝素与Kalpha(V)beta(3)细胞预孵育可增强黏附，而肝素与黏附底物(玻璃连素)预孵育对黏附的影响很小。肝素的作用具有结构特异性，因为低分子肝素和硫酸软骨素对粘附力的促进作用明显较小。这些发现表明，肝素对整合素-配体相互作用的调节是通过它对整合素的作用而发生的。肝素的抑制或刺激作用取决于β亚基类型，其效力由糖胺聚糖的结构特征决定。
Heparin is known to influence the growth, proliferation, and migration of vascular cells, but the precise mechanisms are unknown. We previously demonstrated that unfractionated heparin (UH) binds to the platelet integrin alpha(IIb)beta(3) , and enhances ligand binding. To help define the specificity and site(s) of heparin-integrin interactions, we employed the erythroleukemic K562 cell line, transfected to express specific integrins (alpha(v)beta(3) , alpha(v)beta(5) , and alpha(IIb)beta(3)). By comparing K562 cells expressing a common alpha subunit (Kalpha (v)beta(3) , Kalpha(v)beta(5)) with cells expressing a common beta subunit (Kalpha (v)beta(3) , Kalpha(IIb)beta(3)), we observed that heparin differentially modulated integrin-mediated adhesion to vitronectin. UH at 0.5-7.5 mug/ml consistently enhanced the adhesion of beta(3) expressing cells (Kalpha(v)beta(3) ,Kalpha(IIb)beta(3)). In contrast, UH at 0.5-7.5 mug/ml inhibited Kalpha(v)beta(5) adhesion. Experiments using integrin-blocking antibodies, appropriate control ligands, and nontransfected native K562 cells revealed that heparin's actions were mediated by the specific integrins under study. Preincubation of heparin with Kalpha(v)beta(3) cells enhanced adhesion, while preincubation of heparin with the adhesive substrate (vitronectin) had minimal effect. There was a structural specificity to heparin's effect, in that a low molecular weight heparin and chondroitin sulfate showed significantly less enhancement of adhesion. These findings suggest that heparin's modulation of integrin-ligand interactions occurs through its action on the integrin. The inhibitory or stimulatory effects of heparin depend on the beta subunit type, and the potency is dictated by structural characteristics of the glycosaminoglycan.