Glucagon-Like Peptide 1 Receptor Activation Attenuates Platelet Aggregation and Thrombosis
Glucagon-Like Peptide 1 Receptor Activation Attenuates Platelet Aggregation and Thrombosis
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DOI：
10.2337/db15-1141
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发表时间：
2016-06-01
期刊：
影响因子：
7.7
通讯作者：
Husain, Mansoor
中科院分区：
文献类型：
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作者：
Cameron-Vendrig, Alison;Reheman, Adili;Husain, Mansoor
对接受胰高血糖素样肽1(GLP-1)靶向治疗的糖尿病患者的短期研究表明，心血管事件的数量减少。这种出人意料的快速效应背后的机制尚不清楚。我们从人巨核细胞系(MEG-01)中克隆了GLP-1R全长mRNA，发现GLP-1R在MEG-01细胞中的表达水平高于人肺，但低于人胰腺。与GLP-1和GLP-1R激动剂埃塞那肽孵育后，MEG-01细胞产生cAMP反应，埃塞那肽显著抑制凝血酶、ADP和胶原诱导的血小板聚集。在使用人和小鼠全血的体外灌注室中，与埃塞那肽孵育也可以抑制流动条件下血栓的形成。在小鼠提睾肌动脉激光损伤模型中，单次静脉注射埃塞那肽可抑制正常血糖和高血糖小鼠体内血栓的形成。与接受野生型骨髓移植的小鼠相比，移植缺乏功能性GLP-1R(GLP1R(-/-))的骨髓移植的小鼠血栓形成更大。虽然在移植GLP1R(-/-)小鼠骨髓的小鼠中，埃塞那肽的抗血栓作用部分消失，但在内皮型一氧化氮合酶基因缺陷的小鼠中检测不到这些作用。GLP-1R激动剂抑制血小板功能和防止血栓形成是减少动脉粥样硬化血栓形成的潜在机制。
Short-term studies in subjects with diabetes receiving glucagon-like peptide 1 (GLP-1)-targeted therapies have suggested a reduced number of cardiovascular events. The mechanisms underlying this unexpectedly rapid effect are not known. We cloned full-length GLP-1 receptor (GLP-1R) mRNA from a human megakaryocyte cell line (MEG-01), and found expression levels of GLP-1Rs in MEG-01 cells to be higher than those in the human lung but lower than in the human pancreas. Incubation with GLP-1 and the GLP-1R agonist exenatide elicited a cAMP response in MEG-01 cells, and exenatide significantly inhibited thrombin-, ADP-, and collagen-induced platelet aggregation. Incubation with exenatide also inhibited thrombus formation under flow conditions in ex vivo perfusion chambers using human and mouse whole blood. In a mouse cremaster artery laser injury model, a single intravenous injection of exenatide inhibited thrombus formation in normoglycemic and hyperglycemic mice in vivo. Thrombus formation was greater in mice transplanted with bone marrow lacking a functional GLP-1R (Glp1r(-/-)) compared with those receiving wild-type bone marrow. Although antithrombotic effects of exenatide were partly lost in mice transplanted with bone marrow from Glp1r(-/-) mice, they were undetectable in mice with a genetic deficiency of endothelial nitric oxide synthase. The inhibition of platelet function and the prevention of thrombus formation by GLP-1R agonists represent potential mechanisms for reduced atherothrombotic events.