Highly electronegative LDL from patients with ST-elevation myocardial infarction triggers platelet activation and aggregation
Highly electronegative LDL from patients with ST-elevation myocardial infarction triggers platelet activation and aggregation
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DOI：
10.1182/blood-2013-05-504639
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发表时间：
2013-11-21
期刊：
影响因子：
20.3
通讯作者：
Chen, Chu-Huang
中科院分区：
文献类型：
--
作者：
Chan, Hua-Chen;Ke, Liang-Yin;Chen, Chu-Huang
血小板活化和聚集是导致 ST 段抬高型心肌梗死 (STEMI) 的急性血栓形成的基础。 STEMI 患者的 L5（高负电性低密度脂蛋白 (LDL)）显着升高。因此，我们检查了 L5 在血栓形成中的作用。 STEMI 患者 (n = 30) 的血浆 LDL 通过色谱分离为电负性逐渐增加的 5 个亚组分 (L1-L5)。在体外，L5 比 L1 更能增强二磷酸腺苷刺激的血小板聚集，并诱导血小板-内皮细胞 (EC) 粘附。 L5 还增加血小板中 P-选择素的表达和糖蛋白 (GP) IIb/IIIa 的激活，并降低环磷酸腺苷水平 (n 56，P < .01)。在体内，每周两次向 C57BL/6 小鼠注射 L5 (5 mg/kg)，持续 6 周，可使尾部出血时间缩短 43%（n = 3；与注射 L1 的小鼠相比，P < .01），并增加血小板中的 P-选择素表达和 GPIIb/IIIa 激活。药理学阻断实验表明，L5 通过血小板激活因子受体和凝集素样氧化 LDL 受体 1 发出信号，减弱 Akt 激活并通过蛋白激酶 C-α 触发颗粒释放和 GPIIb/IIIa 激活。 L5 但 L1 不诱导人主动脉 EC 中的组织因子和 P-选择素表达 (P < .01)，从而触发血小板活化并与活化的 EC 聚集。这些发现表明血浆 L5 水平升高可能促进血栓形成，从而导致 STEMI。
Platelet activation and aggregation underlie acute thrombosis that leads to ST-elevation myocardial infarction (STEMI). L5-highly electronegative low-density lipoprotein (LDL)-is significantly elevated in patients with STEMI. Thus, we examined the role of L5 in thrombogenesis. Plasma LDL from patients with STEMI (n = 30) was chromatographically resolved into 5 subfractions (L1-L5) with increasing electronegativity. In vitro, L5 enhanced adenosine diphosphate-stimulated platelet aggregation twofold more than did L1 and induced platelet-endothelial cell (EC) adhesion. L5 also increased P-selectin expression and glycoprotein (GP) IIb/IIIa activation and decreased cyclic adenosine monophosphate levels (n 56, P < .01) in platelets. In vivo, injection of L5 (5 mg/kg) into C57BL/6 mice twice weekly for 6 weeks shortened tail bleeding time by 43%(n = 3; P < .01 vs L1-injected mice) and increased P-selectin expression and GPIIb/IIIa activation in platelets. Pharmacologic blockade experiments revealed that L5 signals through platelet-activating factor receptor and lectin-like oxidized LDL receptor-1 to attenuate Akt activation and trigger granule release and GPIIb/IIIa activation via protein kinase C-alpha. L5 but not L1 induced tissue factor and P-selectin expression in human aortic ECs (P < .01), thereby triggering platelet activation and aggregation with activated ECs. These findings indicate that elevated plasma levels of L5 may promote thrombosis that leads to STEMI.