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Title
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Native, intact glucagon-like peptide-1 is a natural suppressor of thrombus growth under physiological flow conditions
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Author
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Abstract
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| Objective: In patients with diabetes mellitus, increased platelet reactivity predicts cardiac events. Limited evidence suggests that DPP-4 (dipeptidyl peptidase 4) influences platelets via GLP-1 (glucagon-like peptide 1)-dependent effects. Because DPP-4 inhibitors are frequently used in diabetes mellitus to improve the GLP-1-regulated glucose metabolism, we characterized the role of DPP-4 inhibition and of native intact versus DPP-4-cleaved GLP-1 on flow-dependent thrombus formation in mouse and human blood. Approach and Results: An ex vivo whole blood microfluidics model was applied to approach in vivo thrombosis and study collagen-dependent platelet adhesion, activation, and thrombus formation under shear-flow conditions by multiparameter analyses. In mice, in vivo inhibition or genetic deficiency of DPP-4 (Dpp4−/−), but not of GLP-1-receptors (Glp1r−/−), suppressed flow-dependent platelet aggregation. In human blood, GLP-1(7-36), but not DPP-4-cleaved GLP-1(9-36), reduced thrombus volume by 32% and impaired whole blood thrombus formation at both low/venous and high/arterial wall-shear rates. These effects were enforced on ADP costimulation and occurred independently of plasma factors and leukocytes. Human platelets did not contain detectable levels of GLP-1-receptor transcripts. Also, GLP-1(7-36) did not inhibit collagen-induced aggregation under conditions of stirring or stasis of platelets, pointing to a marked flow-dependent role. Conclusions: Native, intact GLP-1 is a natural suppressor of thrombus growth under physiological flow conditions, with DPP-4 inhibition and increased intact GLP-1 suppressing platelet aggregation under flow without a main relevance of GLP-1-receptor on platelets. |
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Language
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English
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Source (journal)
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Arteriosclerosis, thrombosis, and vascular biology / American Heart Association. - Dallas, Tex., 1995, currens
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Publication
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Dallas, Tex.
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2020
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ISSN
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1079-5642
1524-4636
[online]
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DOI
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10.1161/ATVBAHA.119.313645
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Volume/pages
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40
:3
(2020)
, p. E65-E77
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ISI
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000528018700004
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Pubmed ID
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31893947
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Full text (Publisher's DOI)
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Full text (open access)
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Full text (publisher's version - intranet only)
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