Native, Intact Glucagon-Like Peptide-1 Is a Natural Suppressor of Thrombus Growth Under Physiological Flow Conditions.

Sternkopf, Marieke; Nagy, Magdolna; Baaten, Constance C F M J; Kuijpers, Marijke J E; Tullemans, Bibian M E; Wirth, Julia; Theelen, Wendy; Mastenbroek, Tom G; Lehrke, Michael; Winnerling, Benjamin; Baerts, Lesley; Marx, Nikolaus; De Meester, Ingrid; Döring, Yvonne; Cosemans, Judith M E M; Daiber, Andreas; Steven, Sebastian; Jankowski, Joachim; Heemskerk, Johan W M and Noels, Heidi (2020). Native, Intact Glucagon-Like Peptide-1 Is a Natural Suppressor of Thrombus Growth Under Physiological Flow Conditions. Arteriosclerosis, thrombosis, and vascular biology, 40(3), e65-e77. American Heart Association 10.1161/ATVBAHA.119.313645

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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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