RGDV peptide selectively inhibits platelet-dependent thrombus formation in vivo. Studies using a baboon model.
RGDV peptide selectively inhibits platelet-dependent thrombus formation in vivo. Studies using a baboon model.
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RGDV 肽选择性抑制体内血小板依赖性血栓形成。
DOI：
10.1172/jci114256
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发表时间：
1989
期刊：
影响因子：
--
通讯作者：
Hanson,SR
中科院分区：
文献类型：
--
作者：
Cadroy,Y;Houghten,RA;Hanson,SR
由于血小板止血功能介导的部分通过含有RGD（精氨酸-甘氨酸-天冬氨酸）识别序列的粘附蛋白的结合，并由于血小板反应可以抑制在体外由含有RGD的肽，我们在体内评估的RGDV（精氨酸-甘氨酸-天冬氨酸-缬氨酸）四肽的抗血栓形成活性使用狒狒血栓形成模型。血栓形成是由一个装置组成的管状段涂有I型胶原蛋白，其次是两个区域的扩张直径表现出干扰流动和停滞。在中等壁剪切速率（100 s-1）条件下，将血栓形成装置纳入股动静脉分流管中。通过闪烁照相机成像的111 In-血小板和通过计数的125 I-纤维蛋白原/纤维蛋白测定血栓形成。在胶原基质上形成的血栓富含血小板，而在扰动流动区域形成的血栓富含纤维蛋白和红细胞。将RGDV肽输注到血栓形成装置的近端，以维持25、50和100 μ M的局部血浆浓度。输注的RGDV以剂量-反应方式减少血小板和纤维蛋白在胶原基质上的积聚。在最高剂量下，40分钟后血小板和纤维蛋白沉积减少了80%以上（P <0.01）。在干扰流区域，RGDV（100 μ M）减少了85%的血小板沉积（P <0.01），但没有减少纤维蛋白的积累（P <0.3）。类似地，该肽抑制与血栓相关的血小板释放颗粒蛋白（血小板因子4，β-血小板球蛋白; P <0.01），但不能阻止循环血液中纤维蛋白肽A的出现（P> 0.1）。局部输注RGDV未引起血压、出血时间或离体血小板聚集的全身性改变。RGDV肽的抗血栓作用在停止输注后5 min内消失。在对照研究中，输注的RGEV（Arg-Gly-Glu-Val，100 μ M）没有显示出抗血栓形成活性。因此，RGDV选择性地阻断体内血小板依赖性血栓形成。
Since platelet hemostatic functions are mediated in part through the binding of adhesive proteins containing an RGD (Arg-Gly-Asp) recognition sequence, and since platelet reactions may be inhibited in vitro by RGD-containing peptides, we assessed in vivo the antithrombotic activity of RGDV (Arg-Gly-Asp-Val) tetrapeptide using a baboon thrombosis model. Thrombus formation was induced by a device consisting of a tubular segment coated with type I collagen, followed by two regions of expanded diameter exhibiting disturbed flow and stasis. The thrombogenic device was incorporated into femoral arteriovenous shunts under conditions of intermediate wall shear rate (100 s-1). Thrombus formation was measured by scintillation camera imaging of 111In-platelets and by counting of 125I-fibrinogen/fibrin. Thrombus that formed on the collagen substrate was rich in platelets, while thrombus formed in the disturbed flow regions was rich in fibrin and red cells. RGDV peptide was infused proximal to the thrombogenic device to maintain local plasma concentrations of 25, 50, and 100 microM. Infused RGDV decreased the accumulation of both platelets and fibrin on the collagen substrate in a dose-response manner. At the highest dose platelet and fibrin deposition after 40 min was reduced by greater than 80% (P less than 0.01). In the region of disturbed flow, RGDV (100 microM) reduced platelet deposition by 85% (P less than 0.01) but did not reduce the accumulation of fibrin (P less than 0.3). Similarly, the peptide inhibited the release of granular proteins from platelets associated with thrombus (platelet factor 4, beta-thromboglobulin; P less than 0.01), but did not prevent the appearance of fibrinopeptide A in circulating blood (P greater than 0.1). No systemic alterations in blood pressure, bleeding time, or platelet aggregation ex vivo were produced by locally infused RGDV. The antithrombotic effects of RGDV peptide disappeared within 5 min after discontinuing the infusion. In control studies infused RGEV (Arg-Gly-Glu-Val, 100 microM) showed no antithrombotic activity. Thus, RGDV selectively blocks platelet-dependent thrombus formation in vivo.