Higher specificity of the activity of low molecular weight fucoidan for thrombin-induced platelet aggregation
Higher specificity of the activity of low molecular weight fucoidan for thrombin-induced platelet aggregation
复制标题
低分子量岩藻依聚糖对凝血酶诱导的血小板聚集的活性具有更高的特异性
DOI：
10.1016/j.thromres.2010.02.011
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发表时间：
2010-05-01
影响因子：
7.5
通讯作者：
Luo, Dali
中科院分区：
文献类型：
--
作者：
Zhu, Zhixiang;Zhang, Quanbin;Luo, Dali
褐藻多糖具有广泛的生物活性，包括抗凝和抗血栓形成，使其具有潜在的临床应用前景。我们研究了青岛海带中国(F-Q和HMWF-Q)中低分子褐藻糖胶和高分子褐藻糖胶的抗聚集、抗凝血和抗血栓活性及其可能的作用机制。在大鼠和人的血小板上，HMWF-Q表现为促聚集反应，而F-Q(与市售岩藻糖胶(F-S)和肝素一样)对凝血酶诱导的聚集具有抑制作用，IC50为8mU g/mL，约为F-S和肝素的5倍。在活化的部分凝血活酶时间试验中，F-Q(40mU g/m L)的作用弱于F-S(40 m u g/m L)和肝素(7 m u g/m L)；162+/-2.4 S对250+/-13.2 S和300 S，P<；0.01。在体外对凝血酶催化的纤维蛋白原裂解的抑制作用(IC5010mU/mLvs.2.8mUg/mLvs.2.8mU/mLvs.3 mg/kg)也弱于F-S。抗凝血酶(AT)或肝素辅因子II(HCII)均能显著增强F-Q和肝素对凝血酶活性的抑制作用。荧光猝灭和PAGE分析均显示F-S与凝血酶、F-Q或肝素与AT发生直接相互作用。此外，F-S还观察到促聚集作用和凝血酶活性的增强，但F-Q或肝素治疗没有观察到这一作用。这些结果表明，F-Q通过激活AT和HCII来抑制凝血酶，而F-S主要与凝血酶直接相互作用。重要的是，与肝素和F-S相比，F-Q对低聚集的特异性更高，而对抗凝血的影响更弱。因此，F-Q有望成为治疗血栓相关心血管疾病的候选药物。(C)2010爱思唯尔有限公司。保留所有权利。
Algal fucoidans possess a wide variety of biological activities, including anticoagulation and antithrombosis, making them potential candidates for clinical use. We assessed the antiaggregant, anticoagulant and antithrombotic activities and the underlying mechanism of the low-and high-molecular weight fucoidans from the seaweed Laminaria japonica of Qingdao, China (F-Q and HMWF-Q). In the platelets of rats and humans, HMWF-Q demonstrated a pro-aggregation response, whereas F-Q (like the commercially purchased fucoidan (F-S) and heparin), showed an inhibitory effect on thrombin-induced aggregation with an IC50 of 8 mu g/mL, approximately five times lower than those of F-S and heparin. In the activated partial thromboplastin time test, F-Q (40 mu g/mL) demonstrated less potent effect than F-S (40 mu g/mL) and heparin (7 mu g/mL); 162 +/- 2.4 s vs. 250 +/- 13.2 s and > 300 s, p < 0.01, respectively. It was also less effective than F-S on inhibiting thrombin catalyzed fibrinogen cleavage (IC50 10 mu g/mL vs. 2.8 mu g/mL) in vitro and rat thrombosis in vivo at 3 mg/kg (i.v.). The inhibitory effects of F-Q and heparin on thrombin activity were strikingly enhanced by either antithrombin (AT) or heparin cofactor II (HCII). A direct interaction of F-S with thrombin, and F-Q or heparin with AT was demonstrated in both fluorescence quenching and PAGE analysis. Additionally, a pro-aggregation effect and an enhancement of thrombin activity were also observed with F-S, but not with F-Q or heparin, treatment. These results indicate that F-Q inhibits thrombin via activation of AT and HCII, whereas F-S mainly interacts directly with thrombin. Importantly, F-Q shows a higher specificity for hypoaggregation and a weaker effect for anticoagulant profiles than heparin and F-S. Therefore, F-Q could be a promising candidate for the treatment of thrombosis-related cardiovascular diseases. (C) 2010 Elsevier Ltd. All rights reserved.