Marieke Sternkopf1, Magdolna Nagy2, Constance C F M J Baaten1, Marijke J E Kuijpers2, Bibian M E Tullemans2, Julia Wirth1, Wendy Theelen1, Tom G Mastenbroek2, Michael Lehrke3, Benjamin Winnerling1, Lesley Baerts4, Nikolaus Marx3, Ingrid De Meester4, Yvonne Döring5,6,7, Judith M E M Cosemans2, Andreas Daiber8, Sebastian Steven8, Joachim Jankowski1,9, Johan W M Heemskerk2, Heidi Noels1. 1. From the Institute for Molecular Cardiovascular Research (IMCAR) (M.S., C.C.F.M.J.B., J.W., W.T., B.W., J.J., H.N.), University Clinic Aachen, Germany. 2. Department of Biochemistry (M.N., M.J.E.K., B.M.E.T., T.G.M., J.M.E.M.C., J.W.M.H.), Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, The Netherlands. 3. Medical Clinic I (M.L., N.M.), University Clinic Aachen, Germany. 4. Laboratory of Medical Biochemistry, Department of Pharmaceutical Sciences, University of Antwerp, Belgium (L.B., I.D.M.). 5. Institute for Cardiovascular Prevention (IPEK), Ludwig-Maximilians-University (LMU), Munich, Germany (Y.D.). 6. German Center for Cardiovascular Research (DZHK), Partner Site Munich Heart Alliance, Germany (Y.D.). 7. Division of Angiology, Swiss Cardiovascular Centre, Inselspital, Bern University Hospital, University of Bern, Switzerland (Y.D.). 8. Center for Cardiology, University Medical Center of the Johannes Gutenberg-University, Mainz, Germany (A.D., S.S.). 9. Experimental Vascular Pathology (J.J.), Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, The Netherlands.
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.
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.
Authors: M F A Karel; T P Lemmens; B M E Tullemans; S J H Wielders; E Gubbins; D van Beurden; S van Rijt; J M E M Cosemans Journal: Cell Mol Bioeng Date: 2021-10-27 Impact factor: 2.321
Authors: Johanna Helmstädter; Karin Keppeler; Leonie Küster; Thomas Münzel; Andreas Daiber; Sebastian Steven Journal: Br J Pharmacol Date: 2021-05-06 Impact factor: 8.739