Phosphatidylserine-positive erythrocytes bind to immobilized and soluble thrombospondin-1 via its heparin-binding domain.
Phosphatidylserine-positive erythrocytes bind to immobilized and soluble thrombospondin-1 via its heparin-binding domain.
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DOI：
10.1016/j.trsl.2008.07.007
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发表时间：
2008-10
期刊：
影响因子：
--
通讯作者：
Setty BN
中科院分区：
文献类型：
--
作者：
Gayen Betal S;Setty BN
磷脂酰丝氨酸（PS）依赖性红细胞与内皮及内皮下基质成分的黏附部分是通过血小板反应蛋白（TSP）介导的。虽然TSP具有多个细胞结合结构域，但TSP上的PS结合位点尚不清楚。由于阴离子肝素的一个细胞结合结构域位于氨基末端，我们假设PS阳性红细胞（PS + ve - RBCs）与该结构域结合。我们证明，肝素及其低分子量衍生物依诺肝素（0.5 - 50u/ml）以浓度依赖的方式抑制PS + ve - RBC与固定化TSP的黏附（抑制率为21 - 77%，P < 0.05）。用抗肝素结合结构域的抗体对固定化TSP进行预孵育可阻断PS + ve - RBC与TSP的黏附。识别TSP上胶原蛋白和羧基末端CD47结合结构域的抗体对这一过程没有影响。虽然用含有特定肝素结合基序KKTRG的肝素结合结构域的TSP肽对PS + ve - RBCs进行预孵育可抑制PS + ve - 红细胞与基质TSP的黏附（P < 0.001），但这些固定化形式的肽支持PS介导的红细胞黏附。缺乏结合基序的TSP肽既不抑制也不支持PS + ve - RBC的黏附。其他实验表明，可溶性TSP也通过其肝素结合结构域与PS + ve - RBCs相互作用。我们的研究结果表明，PS阳性红细胞通过肝素结合结构域与固定化和可溶性TSP结合，并且肝素和依诺肝素在临床相关浓度下可阻断这种相互作用。其他研究表明，肝素可抑制P - 选择素和可溶性TSP介导的镰状红细胞与内皮细胞的黏附。我们的研究结果与先前记录的发现相结合，为肝素或其低分子量衍生物作为治疗镰状细胞病患者血管闭塞性疼痛的治疗药物的临床应用提供了合理依据。
Phosphatidylserine (PS)-dependent erythrocyte adhesion to endothelium and sub-endothelial matrix components is mediated in part via thrombospondin (TSP). While TSP exhibits multiple cell-binding domains, the PS-binding site on TSP is unknown. Since a cell-binding domain for anionic heparin is located at the amino-terminus, we hypothesized that PS-positive red cells (PS+ve-RBCs) bind to this domain. We demonstrate that both heparin and its low-molecular-weight derivative enoxaparin (0.5-50u/ml) inhibited PS+ve-RBC adhesion to immobilized TSP in a concentration-dependent manner (21-77% inhibition, P<0.05). Pre-incubation of immobilized TSP with an antibody against the heparin-binding domain blocked PS+ve-RBC adhesion to TSP. Antibodies that recognize the collagen- and the carboxy-terminal CD47-binding domain on TSP had no effect on this process. While pre-incubation of PS+ve-RBCs with TSP-peptides from the heparin-binding domain containing the specific heparin-binding motif KKTRG inhibited PS+ve-erythrocyte adhesion to matrix TSP (P<0.001), these peptides in the immobilized form supported PS-mediated erythrocyte adhesion. A TSP-peptide lacking the binding-motif neither inhibited nor supported PS+ve-RBC adhesion. Additional experiments show that soluble-TSP also interacted with PS+ve-RBCs via its heparin-binding domain. Our results demonstrate that PS-positive erythrocytes bind to both immobilized and soluble TSP via its heparin-binding domain and that both heparin and enoxaparin, at clinically relevant concentrations, block this interaction. Other studies have shown that heparin inhibited P-selectin- and soluble-TSP-mediated sickle erythrocyte adhesion to endothelial cells. Our results taken together with the previously documented findings provide a rational basis for clinical use of heparin or its low-molecular-weight derivatives as therapeutic agents in treating vaso-occlusive pain in patients with sickle cell disease.
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DOI：
10.1073/pnas.80.4.998
发表时间：
1983-01-01
期刊：
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA-BIOLOGICAL SCIENCES
影响因子：
--
作者：
JAFFE, EA;RUGGIERO, JT;MOSHER, DF
通讯作者：
MOSHER, DF
影响因子：
20.3
作者：
Hofstra, TC;Kalra, VK;Coates, TD
通讯作者：
Coates, TD
影响因子：
3.3
作者：
ADAMS, JC;LAWLER, J
通讯作者：
LAWLER, J
影响因子：
15.9
作者：
Brittain, JE;Mlinar, KJ;Parise, LV
通讯作者：
Parise, LV
影响因子：
20.3
作者：
Hillery, CA;Du, MC;Scott, JP
通讯作者：
Scott, JP