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RESEARCH PRODUCT
Native, Intact Glucagon-Like Peptide 1 Is a Natural Suppressor of Thrombus Growth Under Physiological Flow Conditions
Marijke J.e. KuijpersBibian M. E. TullemansJulia WirthMichael LehrkeIngrid De MeesterSebastian StevenAndreas DaiberLesley BaertsMagdolna NagyMarieke SternkopfNikolaus MarxJudith M.e.m. CosemansYvonne DöringYvonne DöringConstance C.f.m.j. BaatenBenjamin WinnerlingJoachim JankowskiHeidi NoelsWendy TheelenJohan W. M. HeemskerkTom G. Mastenbroeksubject
Blood Platelets0301 basic medicineendocrine systemmedicine.medical_specialtyPlatelet AggregationPLATELET ACTIVATIONLinagliptin030204 cardiovascular system & hematologyDPP4Glucagon-Like Peptide-1 Receptorlaw.invention03 medical and health sciences0302 clinical medicinedipeptidyl peptidase 4Fibrinolytic AgentslawInternal medicineDiabetes mellitusmedicineAnimalsHumansPlateletIn patientThrombusglucose610 Medicine & healthDipeptidyl peptidase-4Mice KnockoutDipeptidyl-Peptidase IV InhibitorsChemistryPharmacology. TherapySitagliptin Phosphatedigestive oral and skin physiologyThrombosismedicine.diseaseGlucagon-like peptide-1Peptide Fragmentsglucagon-like peptide 1Mice Inbred C57BLMICE030104 developmental biologyEndocrinologyPhysiological flowdiabetes mellitusplateletsSuppressorHuman medicineCardiology and Cardiovascular MedicineSignal Transductiondescription
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.
| year | journal | country | edition | language |
|---|---|---|---|---|
| 2020-03-01 |