title: Glucagon-Like Peptide 1 Receptor Activation Attenuates Platelet Aggregation and Thrombosis.
abstract: 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.
authors.affiliation: 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.
authors.forename: Alison
authors.initials: A
authors.lastname: Cameron-Vendrig
authors.affiliation: Keenan Research Centre, Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, Ontario, Canada.
authors.forename: Adili
authors.initials: A
authors.lastname: Reheman
authors.affiliation: Toronto General Research Institute, University Health Network, Toronto, Ontario, Canada.
authors.forename: M Ahsan
authors.initials: MA
authors.lastname: Siraj
authors.affiliation: Heart and Stroke Richard Lewar Centre of Excellence, University of Toronto, Toronto, Ontario, Canada Keenan Research Centre, Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, Ontario, Canada Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Xiaohong Ruby
authors.initials: XR
authors.lastname: Xu
authors.affiliation: Keenan Research Centre, Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, Ontario, Canada Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Yiming
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Keenan Research Centre, Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, Ontario, Canada.
authors.forename: Xi
authors.initials: X
authors.lastname: Lei
authors.affiliation: 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.
authors.forename: Talat
authors.initials: T
authors.lastname: Afroze
authors.affiliation: Heart and Stroke Richard Lewar Centre of Excellence, University of Toronto, Toronto, Ontario, Canada Toronto General Research Institute, University Health Network, Toronto, Ontario, Canada Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Eric
authors.initials: E
authors.lastname: Shikatani
authors.affiliation: 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.
authors.forename: Omar
authors.initials: O
authors.lastname: El-Mounayri
authors.affiliation: 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.
authors.forename: Hossein
authors.initials: H
authors.lastname: Noyan
authors.affiliation: Center for Systems Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA Department of Systems Biology, Harvard Medical School, Boston, MA.
authors.forename: Ralph
authors.initials: R
authors.lastname: Weissleder
authors.affiliation: Department of Physiology, University of Toronto, Toronto, Ontario, Canada Heart and Stroke Richard Lewar Centre of Excellence, University of Toronto, Toronto, Ontario, Canada Keenan Research Centre, Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, Ontario, Canada Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada Department of Medicine, University of Toronto, Toronto, Ontario, Canada Canadian Blood Services, Toronto, Ontario, Canada.
authors.forename: Heyu
authors.initials: H
authors.lastname: Ni
authors.affiliation: 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 Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada Department of Medicine, University of Toronto, Toronto, Ontario, Canada Ted Rogers Centre for Heart Research, University Health Network, Toronto, Ontario, Canada mansoor.husain@uhn.ca.
authors.forename: Mansoor
authors.initials: M
authors.lastname: Husain
mesh_terms: D000818:Animals; D002460:Cell Line; D000077270:Exenatide; D052216:Glucagon-Like Peptide 1 / Q000378:metabolism; D000067757:Glucagon-Like Peptide-1 Receptor / Q000378:metabolism*; D006801:Humans; D008168:Lung / Q000378:metabolism; D051379:Mice; D052250:Nitric Oxide Synthase Type III / Q000172:deficiency; D010179:Pancreas / Q000378:metabolism; D010455:Peptides / Q000494:pharmacology*; D010974:Platelet Aggregation / Q000187:drug effects*; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D013927:Thrombosis / Q000517:prevention & control*; D014688:Venoms / Q000494:pharmacology*; D000097789:Glucagon-Like Peptide-1 Receptor Agonists
chemical_list: D000067757:Glucagon-Like Peptide-1 Receptor; D010455:Peptides; D010975:Platelet Aggregation Inhibitors; D014688:Venoms; D052216:Glucagon-Like Peptide 1; D000077270:Exenatide; D052250:Nitric Oxide Synthase Type III; D000097789:Glucagon-Like Peptide-1 Receptor Agonists