title: Glucagon-like peptide-1 receptor signalling reduces microvascular thrombosis, nitro-oxidative stress and platelet activation in endotoxaemic mice.
abstract: Excessive inflammation in sepsis causes microvascular thrombosis and thrombocytopenia associated with organ dysfunction and high mortality. The present studies aimed to investigate whether inhibition of dipeptidyl peptidase-4 (DPP-4) and supplementation with glucagon-like peptide-1 (GLP-1) receptor agonists improved endotoxaemia-associated microvascular thrombosis via immunomodulatory effects.
  
  
  
  Endotoxaemia was induced in C57BL/6J mice by a single injection of LPS (17.5 mg kg-1for survival and 10 mg kg-1for all other studies). For survival studies, treatment was started 6 h after LPS injection. For all other studies, drugs were injected 48 h before LPS treatment.
  
  
  
  Mice treated with LPS alone showed severe thrombocytopenia, microvascular thrombosis in the pulmonary circulation (fluorescence imaging), increased LDH activity, endothelial dysfunction and increased markers of inflammation in aorta and whole blood (leukocyte-dependent oxidative burst, nitrosyl-iron haemoglobin, a marker of nitrosative stress, and expression of inducible NOS). Treatment with the DPP-4 inhibitor linagliptin or the GLP-1 receptor agonist liraglutide, as well as genetic deletion of DPP-4 (DPP4-/-mice) improved all these parameters. In GLP-1 receptor-deficient mice, both linagliptin and liraglutide lost their beneficial effects and improvement of prognosis. Incubation of platelets and cultured monocytes (containing GLP-1 receptor protein) with GLP-1 receptor agonists inhibited the monocytic oxidative burst and platelet activation, with a GLP-1 receptor-dependent elevation of cAMP levels and PKA activation.
  
  
  
  GLP-1 receptor activation in platelets by linagliptin and liraglutide strongly attenuated endotoxaemia-induced microvascular thrombosis and mortality by a cAMP/PKA-dependent mechanism, preventing systemic inflammation, vascular dysfunction and end organ damage.
  
  
  
  This article is part of a themed section on Redox Biology and Oxidative Stress in Health and Disease. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.12/issuetoc.
authors.affiliation: Centre for Cardiology, Cardiology I, University Medical Centre of the Johannes Gutenberg University, Mainz, Germany.|Center for Thrombosis and Hemostasis, University Medical Centre of the Johannes Gutenberg University, Mainz, Germany.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Steven
authors.affiliation: Center for Thrombosis and Hemostasis, University Medical Centre of the Johannes Gutenberg University, Mainz, Germany.
authors.forename: Kerstin
authors.initials: K
authors.lastname: Jurk
authors.affiliation: Centre for Cardiology, Cardiology I, University Medical Centre of the Johannes Gutenberg University, Mainz, Germany.
authors.forename: Maximilian
authors.initials: M
authors.lastname: Kopp
authors.affiliation: Centre for Cardiology, Cardiology I, University Medical Centre of the Johannes Gutenberg University, Mainz, Germany.
authors.forename: Swenja
authors.initials: S
authors.lastname: Kröller-Schön
authors.affiliation: Centre for Cardiology, Cardiology I, University Medical Centre of the Johannes Gutenberg University, Mainz, Germany.
authors.forename: Yuliya
authors.initials: Y
authors.lastname: Mikhed
authors.affiliation: Center for Thrombosis and Hemostasis, University Medical Centre of the Johannes Gutenberg University, Mainz, Germany.
authors.forename: Kathrin
authors.initials: K
authors.lastname: Schwierczek
authors.affiliation: Centre for Cardiology, Cardiology I, University Medical Centre of the Johannes Gutenberg University, Mainz, Germany.
authors.forename: Siyer
authors.initials: S
authors.lastname: Roohani
authors.affiliation: Centre for Cardiology, Cardiology I, University Medical Centre of the Johannes Gutenberg University, Mainz, Germany.
authors.forename: Fatemeh
authors.initials: F
authors.lastname: Kashani
authors.affiliation: Centre for Cardiology, Cardiology I, University Medical Centre of the Johannes Gutenberg University, Mainz, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Oelze
authors.affiliation: Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Klein
authors.affiliation: Center for Thrombosis and Hemostasis, University Medical Centre of the Johannes Gutenberg University, Mainz, Germany.
authors.forename: Sergey
authors.initials: S
authors.lastname: Tokalov
authors.affiliation: Center for Thrombosis and Hemostasis, University Medical Centre of the Johannes Gutenberg University, Mainz, Germany.|Institute of Clinical Chemistry and Laboratory Medicine, University Medical Centre of the Johannes Gutenberg University, Mainz, Germany.
authors.forename: Sven
authors.initials: S
authors.lastname: Danckwardt
authors.affiliation: I. Department of Internal Medicine, University Medical Centre of the Johannes Gutenberg University, Mainz, Germany.
authors.forename: Susanne
authors.initials: S
authors.lastname: Strand
authors.affiliation: Centre for Cardiology, Cardiology I, University Medical Centre of the Johannes Gutenberg University, Mainz, Germany.|Center for Thrombosis and Hemostasis, University Medical Centre of the Johannes Gutenberg University, Mainz, Germany.
authors.forename: Philip
authors.initials: P
authors.lastname: Wenzel
authors.affiliation: Centre for Cardiology, Cardiology I, University Medical Centre of the Johannes Gutenberg University, Mainz, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Münzel
authors.affiliation: Centre for Cardiology, Cardiology I, University Medical Centre of the Johannes Gutenberg University, Mainz, Germany.|Center for Thrombosis and Hemostasis, University Medical Centre of the Johannes Gutenberg University, Mainz, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Daiber
mesh_terms: D000818:Animals; D018819:Dipeptidyl Peptidase 4 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D019446:Endotoxemia / Q000139:chemically induced / Q000378:metabolism*; D000067757:Glucagon-Like Peptide-1 Receptor / Q000172:deficiency / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000008:administration & dosage; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D055806:Microvessels / Q000187:drug effects / Q000378:metabolism*; D009569:Nitric Oxide / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects; D015539:Platelet Activation / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D020246:Venous Thrombosis / Q000139:chemically induced / Q000378:metabolism*; D000097789:Glucagon-Like Peptide-1 Receptor Agonists
chemical_list: C000593834:Glp1r protein, mouse; D000067757:Glucagon-Like Peptide-1 Receptor; D008070:Lipopolysaccharides; D009569:Nitric Oxide; D018819:Dipeptidyl Peptidase 4; C545245:Dpp4 protein, mouse; D000097789:Glucagon-Like Peptide-1 Receptor Agonists