Glucagon-Like Peptide 1 Receptor Activation Attenuates Platelet Aggregation and Thrombosis.

Short-term studies in diabetic subjects receiving glucagon-like peptide-1 (GLP-1)-targeted therapies have suggested reduced 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-1R in MEG-01 cells to be higher than human lung but lower than 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 -/- ), as compared to those receiving wild-type bone marrow. Although anti-thrombotic effects of exenatide were partly lost in mice transplanted with bone marrow from Glp1r -/- mice, they were undetectable in mice with genetic deficiency of eNOS. Inhibition of platelet function and prevention of thrombus formation by GLP-1R agonists represent potential mechanisms for reduced atherothrombotic events. ( 198 words )