title: Glucagon-like peptide 1-related peptides increase nitric oxide effects to reduce platelet activation.
abstract: Glucagon-like peptide 1 (GLP-1) is object of intensive investigation for not only its metabolic effects but also the protective vascular actions. Since platelets exert a primary role in the pathogenesis of atherosclerosis, inflammation and vascular complications, we investigated whether GLP-1 directly influences platelet reactivity. For this purpose, in platelets from 72 healthy volunteers we evaluated GLP-1 receptor (GLP-1R) expression and the effects of a 15-minute incubation with the native form GLP-1(7-36), the N-terminally truncated form GLP-1(9-36) and the GLP-1 analogue Liraglutide (100 nmol/l) on: i) aggregation induced by collagen or arachidonic acid (AA); ii) platelet function under shear stress; iii) cGMP and cAMP synthesis and cGMP-dependent protein kinase (PKG)-induced Vasodilator-Stimulated-Phosphoprotein (VASP) phosphorylation; iv) activation of the signalling molecules Phosphatidylinositol 3-Kinase (PI3-K)/Akt and Mitogen Activated Protein Kinase (MAPK)/ERK-1/2; and v) oxidative stress. Experiments were repeated in the presence of the nitric oxide donor Na-nitroprusside. We found that platelets constitutively express GLP-1R and that, independently of GLP-1R, GLP-1(7-36), GLP-1(9-36) and Liraglutide exert platelet inhibitory effects as shown by: a) increased NO-antiaggregating effects, b) increased the activation of the cGMP/PKG/VASP pathway, c) reduced the activation of PI3-K/Akt and MAPK/ERK-2 pathways, d) reduced the AA-induced oxidative stress. When the experiments were repeated in the presence of the antagonist of GLP-1R Exendin(9-39), the platelet inhibitory effects were maintained, thus indicating a mechanism independent of GLP-1R. In conclusion, GLP-1(7-36), its degradation product GLP-1(9-36) and Liraglutide exert similar inhibitory effects on platelet activation, suggesting a potential protective effect on the cardiovascular system.
authors.forename: Cristina
authors.initials: C
authors.lastname: Barale
authors.forename: Simona
authors.initials: S
authors.lastname: Buracco
authors.forename: Franco
authors.initials: F
authors.lastname: Cavalot
authors.forename: Chiara
authors.initials: C
authors.lastname: Frascaroli
authors.forename: Angelo
authors.initials: A
authors.lastname: Guerrasio
authors.affiliation: Dr. Isabella Russo, PhD, Internal Medicine and Metabolic Disease Unit, Department of Clinical and Biological Sciences of the Turin University, San Luigi Gonzaga Hospital, 10043 Orbassano (Turin), Italy, Tel.: + 39 011 9026622, Fax: + 39 011 9038639, E-mail: isabella.russo@unito.it.
authors.forename: Isabella
authors.initials: I
authors.lastname: Russo
mesh_terms: D000328:Adult; D001792:Blood Platelets / Q000378:metabolism* / Q000473:pathology; D015815:Cell Adhesion Molecules / Q000378:metabolism; D002478:Cells, Cultured; D006152:Cyclic GMP / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy / Q000378:metabolism*; D005260:Female; D052216:Glucagon-Like Peptide 1 / Q000378:metabolism*; D000067757:Glucagon-Like Peptide-1 Receptor / Q000378:metabolism; D006801:Humans; D000069450:Liraglutide / Q000494:pharmacology; D008297:Male; D008840:Microfilament Proteins / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism*; D009599:Nitroprusside / Q000494:pharmacology; D010446:Peptide Fragments / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation; D015539:Platelet Activation; D015398:Signal Transduction; D000098662:Vasodilator-Stimulated Phosphoprotein
chemical_list: D015815:Cell Adhesion Molecules; C000593833:GLP1R protein, human; D000067757:Glucagon-Like Peptide-1 Receptor; D008840:Microfilament Proteins; D010446:Peptide Fragments; D010750:Phosphoproteins; D000098662:Vasodilator-Stimulated Phosphoprotein; C055453:glucagon-like peptide 1 (7-36)amide; D009599:Nitroprusside; D009569:Nitric Oxide; D000069450:Liraglutide; D052216:Glucagon-Like Peptide 1; D019869:Phosphatidylinositol 3-Kinases; D006152:Cyclic GMP
keywords: Liraglutide; Platelets; diabetes; glucagone-like peptide 1; nitric oxide