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

Marieke Sternkopf, Magdolna Nagy, Constance C. F. M. J. Baaten, Marijke J. E. Kuijpers, Bibian M. E. Tullemans, Julia Wirth, Wendy Theelen, Tom G. Mastenbroek, Michael Lehrke, Benjamin Winnerling, Lesley Baerts, Nikolaus Marx, Ingrid De Meester, Yvonne Doring, Judith M. E. M. Cosemans, Andreas Daiber, Sebastian Steven, Joachim Jankowski, Johan W. M. Heemskerk, Heidi Noels*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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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.

Original languageEnglish
Pages (from-to)E65-E77
Number of pages13
JournalArteriosclerosis Thrombosis and Vascular Biology
Volume40
Issue number3
DOIs
Publication statusPublished - Mar 2020

Keywords

  • diabetes mellitus
  • dipeptidyl peptidase 4
  • glucagon-like peptide 1
  • glucose
  • platelets
  • PLATELET ACTIVATION
  • DPP4
  • MICE

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