Salvianolic acid A inhibits platelet activation and arterial thrombosis via inhibition of phosphoinositide 3-kinase
Salvianolic acid A inhibits platelet activation and arterial thrombosis via inhibition of phosphoinositide 3-kinase
复制标题
丹酚酸 A 通过抑制磷酸肌醇 3-激酶抑制血小板活化和动脉血栓形成
DOI：
10.1111/j.1538-7836.2010.03859.x
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发表时间：
2010-06-01
影响因子：
10.4
通讯作者：
Hu, H.
中科院分区：
文献类型：
--
作者：
Huang, Z. S.;Zeng, C. L.;Hu, H.
背景与目的：丹酚酸A是亚洲医学中广泛用于治疗动脉粥样硬化血栓形成疾病的草本植物丹参根部的水溶性成分。由于血小板在动脉粥样硬化血栓形成中起关键作用，我们研究了SAA对血小板活化的影响及其可能的机制。方法和结果：SAA剂量依赖地抑制ADP、凝血酶、胶原和U46619诱导的血小板聚集。降低ADP诱导的血小板P-选择素表达和纤维蛋白原结合，从而抑制ADP诱导的血小板-白细胞聚集。SAA还抑制了血小板在纤维蛋白原上的扩散，这是一个由外向内信号介导的过程。在动脉切变率为1000 S(-1)的条件下，SAA可使血小板与胶原表面的粘附率降低约40%。Western印迹分析表明，SAA与磷脂酰肌醇3-激酶(PI3K)抑制剂LY294002和TGX-221一样，通过减少Akt的磷酸化而有效地抑制PI3K。在动脉血栓形成的小鼠模型中，SAA延长了野生型小鼠肠系膜动脉阻断时间(35+/-2min和56+/-4min；P<；0.01)。有趣的是，SAA甚至可以对抗Ldlr(Tm1Her)突变小鼠动脉阻断时间的缩短(21+/-2分钟，45+/-4分钟；P<；0.01)。结论：SAA通过抑制PI3K抑制血小板活化，从而抑制体内动脉血栓的形成。我们的数据表明，SAA可能被开发为预防血栓性疾病的一种新的治疗药物。
Background and objective: Salvianolic acid A (SAA) is a water-soluble component from the root of Salvia miltiorrhiza Bunge, a herb that is widely used for atherothrombotic disease treatment in Asian medicine. As platelets play pivotal roles in atherothrombogenesis, we studied the effect of SAA on platelet activation and its underlying mechanisms. Methods and Results: SAA dose-dependently inhibited platelet aggregation induced by ADP, thrombin, collagen and U46619. It reduced ADP-enhanced platelet P-selectin expression and fibrinogen binding, which consequently hampered ADP-induced platelet-leukocyte aggregation. SAA also inhibited platelet spreading on fibrinogen, a process mediated by outside-in signaling. Under an arterial shear rate of 1000 s(-1), SAA decreased platelet adhesion on collagen surfaces by similar to 40%. Western blot analysis showed that SAA, like the phosphoinositide 3-kinase (PI3K) inhibitors LY294002 and TGX-221, potently inhibited PI3K, as shown by reduced Akt phosphorylation. The in vitro findings were further evaluated in the mouse model of arterial thrombosis, in which SAA prolonged the mesenteric arterial occlusion time in wild-type mice (35 +/- 2 min without SAA and 56 +/- 4 min with SAA; P < 0.01). Interestingly, SAA could even counteract the shortened arterial occlusion time in Ldlr(tm1Her) mutant mice (21 +/- 2 min without SAA and 45 +/- 4 min with SAA; P < 0.01). Conclusions: SAA inhibits platelet activation via the inhibition of PI3K, and attenuates arterial thrombus formation in vivo. Our data suggest that SAA may be developed as a novel therapeutic agent for the prevention of thrombotic disorders.