期刊
ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY
卷 40, 期 3, 页码 E65-E77出版社
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/ATVBAHA.119.313645
关键词
diabetes mellitus; dipeptidyl peptidase 4; glucagon-like peptide 1; glucose; platelets
资金
- German Research Foundation [DFG SFB/TRR219-M05, SFB/TRR219-C04, SFB/TRR219-M03, SFB1123-A1, STE2528/2-1]
- Interdisciplinary Centre for Clinical Research (IZKF) within the faculty of Medicine at the RWTH Aachen University [IZKF K7-1, IZKF 105/13]
- CORONA foundation
- Interreg V Euregio Meuse-Rhine program (Poly-Valve)
- Alexander von Humboldt foundation
- Netherlands Organization for Scientific Research (NWO) Vidi [91716421]
- Dutch Heart Foundation [2015T79]
- GOA BOF 2015 grant of the University of Antwerp [30729]
- Cardiovascular Centre (HVC) Maastricht
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.
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