Department of Physiology, University of Toronto, Toronto, Ontario, Canada Heart and Stroke Richard Lewar Centre of Excellence, University of Toronto, Toronto, Ontario, Canada Toronto General Research Institute, University Health Network, Toronto, Ontario, Canada Peter Munk Cardiac Centre, University Health Network, Toronto, Ontario, Canada Keenan Research Centre, Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, Ontario, Canada.
Keenan Research Centre, Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, Ontario, Canada.
Diabetes. 2016 Jun;65(6):1714-23. doi: 10.2337/db15-1141. Epub 2016 Mar 2.
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.
短期研究表明，接受胰高血糖素样肽 1（GLP-1）靶向治疗的糖尿病患者发生心血管事件的数量减少。但目前尚不清楚这种异常快速作用的机制。我们从人类巨核细胞系（MEG-01）中克隆了全长 GLP-1 受体（GLP-1R）mRNA，并发现 GLP-1R 在 MEG-01 细胞中的表达水平高于肺，但低于胰腺。用 GLP-1 和 GLP-1R 激动剂 exenatide 孵育 MEG-01 细胞可引起 cAMP 反应，exenatide 可显著抑制凝血酶、ADP 和胶原诱导的血小板聚集。用 exenatide 孵育还可抑制人及鼠全血在离体灌注室中流动条件下形成血栓。在小鼠提睾肌动脉激光损伤模型中，单次静脉注射 exenatide 可抑制正常血糖和高血糖小鼠体内血栓形成。与接受野生型骨髓的小鼠相比，缺乏功能性 GLP-1R（Glp1r(-/-)）的骨髓移植小鼠形成的血栓更多。虽然 exenatide 的抗血栓作用在接受 Glp1r(-/-) 骨髓移植的小鼠中部分丧失，但在内皮型一氧化氮合酶基因缺失的小鼠中则无法检测到。GLP-1R 激动剂抑制血小板功能和预防血栓形成代表了减少动脉血栓形成事件的潜在机制。
