Native, Intact Glucagon-Like Peptide 1 Is a Natural Suppressor of Thrombus Growth Under Physiological Flow Conditions. Issue 3 (March 2020)

• Record Type: Journal Article
• Authors: 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.; Noels, Heidi
• Is Part Of: Arteriosclerosis, thrombosis, and vascular biology. Volume 40:Issue 3(2020)
• Publication Date: 2020-03
• Subjects: diabetes mellitus -- dipeptidyl peptidase 4 -- glucagon-like peptide 1 -- glucose -- platelets; Arteriosclerosis -- Periodicals; Thrombosis -- Periodicals; Blood-vessels -- Pathophysiology -- Periodicals; Electronic journals; 616.13
• DOI: 10.1161/ATVBAHA.119.313645
• Languages: English
• ISSNs: 1079-5642

Abstract

Abstract : 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 upon 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. Abstract : Supplemental Digital Content is available in the text.