TY - JOUR
T1 - Native, Intact Glucagon-Like Peptide 1 Is a Natural Suppressor of Thrombus Growth Under Physiological Flow Conditions
AU - Sternkopf, Marieke
AU - Nagy, Magdolna
AU - Baaten, Constance C. F. M. J.
AU - Kuijpers, Marijke J. E.
AU - Tullemans, Bibian M. E.
AU - Wirth, Julia
AU - Theelen, Wendy
AU - Mastenbroek, Tom G.
AU - Lehrke, Michael
AU - Winnerling, Benjamin
AU - Baerts, Lesley
AU - Marx, Nikolaus
AU - De Meester, Ingrid
AU - Doring, Yvonne
AU - Cosemans, Judith M. E. M.
AU - Daiber, Andreas
AU - Steven, Sebastian
AU - Jankowski, Joachim
AU - Heemskerk, Johan W. M.
AU - Noels, Heidi
N1 - Funding Information:
This work was supported by the German Research Foundation (DFG SFB/TRR219-M05 to H. Noels and N. Marx; SFB/TRR219-C04 to J. Jankowski; SFB/TRR219-M03 to M. Lehrke and N. Marx; SFB1123-A1 to Y. Döring; and STE2528/2-1 to S. Steven); by a grant from the Interdisciplinary Centre for Clinical Research (IZKF) within the faculty of Medicine at the RWTH Aachen University (IZKF K7-1 to H. Noels and IZKF 105/13 to W. Theelen) and by a grant of the CORONA foundation to N. Marx and M. Lehrke. M. Nagy, M.J.E. Kuijpers, and J.W.M. Heemskerk received funding from the Cardiovascular Centre (HVC) Maastricht and the Interreg V Euregio Meuse-Rhine program (Poly-Valve). C.C.F.M.J. Baaten was supported by the Alexander von Humboldt foundation. The Netherlands Organization for Scientific Research (NWO) Vidi 91716421 to J.M.E.M. Cosemans and the Dutch Heart Foundation 2015T79 to T.G. Mastenbroek and J.M.E.M. Cosemans. I.De Meester was supported by a GOA BOF 2015 grant (No. 30729) of the University of Antwerp.
Publisher Copyright:
© 2020 American Heart Association, Inc.
PY - 2020/3
Y1 - 2020/3
N2 - 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.
AB - 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.
KW - diabetes mellitus
KW - dipeptidyl peptidase 4
KW - glucagon-like peptide 1
KW - glucose
KW - platelets
KW - PLATELET ACTIVATION
KW - DPP4
KW - MICE
U2 - 10.1161/atvbaha.119.313645
DO - 10.1161/atvbaha.119.313645
M3 - Article
C2 - 31893947
SN - 1079-5642
VL - 40
SP - E65-E77
JO - Arteriosclerosis Thrombosis and Vascular Biology
JF - Arteriosclerosis Thrombosis and Vascular Biology
IS - 3
ER -