Glucagon‐like peptide‐1 receptor signalling reduces microvascular thrombosis, nitro‐oxidative stress and platelet activation in endotoxaemic mice

Steven, Sebastian; Jurk, Kerstin; Kopp, Maximilian; Kröller‐Schön, Swenja; Mikhed, Yuliya; Schwierczek, Kathrin; Roohani, Siyer; Kashani, F. Ravandi; Oelze, Matthias; Klein, Thomas; Tokalov, Sergey V.; Danckwardt, Sven; Strand, Susanne; Wenzel, Philip; Münzel, Thomas; Daiber, Andreas

doi:10.1111/bph.13549

Cited by 72 publications

(89 citation statements)

References 51 publications

(64 reference statements)

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“…However, previous investigations have suggested that exendin‐4 and the DPP‐4 inhibitor, linagliptin, potentiate ACh relaxations in rat mesenteric arteries exposed to high glucose by a mechanism decreasing vascular superoxide levels (Salheen et al ., ). Also, native GLP‐1 decreased monocyte‐derived oxidative stress (Steven et al ., ). In the present study, a SOD mimetic, tempol, leftward‐shifted the concentration–response curves for ACh in arteries exposed to high glucose, suggesting vascular superoxide levels played a role in high glucose impairment of ACh relaxation.…”

Section: Discussionmentioning

confidence: 97%

“…Therefore, the effect on vascular tone of GLP‐1 is unclear, and a possible effect of GLP‐1 on the peripheral autonomic nervous system has not been examined despite the fact that several other gut‐derived peptides regulate the release of noradrenaline in the vasculature (Gradin et al ., ). Moreover, hyperglycaemia generates ROS which have been proposed to impair endothelium‐dependent relaxation, and growing evidence reveals that GLP‐1 receptor stimulation may reduce ROS (Salheen et al ., ; Steven et al ., ) and hence improve endothelial function (Salheen et al ., ).…”

Section: Introductionmentioning

confidence: 99%

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Different mechanisms involved in liraglutide and glucagon‐like peptide‐1 vasodilatation in rat mesenteric small arteries

Bangshaab

Gutiérrez

Huynh

et al. 2018

British J Pharmacology

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Background and Purpose Glucagon‐like peptide‐1 (GLP‐1) is an incretin hormone that regulates insulin biosynthesis and secretion in a glucose‐dependent manner and has been reported to induce vasodilatation. Here, we examined the possible vasorelaxant effect of GLP‐1 and its underlying mechanisms. Experimental Approach Rat mesenteric arteries (diameter ≈ 200–400 μm) and human s.c. arteries were mounted in microvascular myographs for isometric tension recordings. The effect of GLP‐1 on vascular responses was examined under normoglycaemic conditions and at high glucose concentrations. Key Results In rat mesenteric arteries and human s.c. arteries without branches, physiological concentrations (1–100 nM) of GLP‐1(7‐36) and liraglutide failed to cause relaxation or affect contractions evoked by electrical field stimulation. In contrast to GLP‐1(7‐36), liraglutide induced relaxations antagonized by the GLP‐1 receptor antagonist, exendin‐(9‐39), in branched mesenteric arteries. In contrast to liraglutide, GLP‐1 leftward shifted the concentration relaxation curves for bradykinin in s.c. arteries from patients with peripheral arterial disease, an effect resistant to exendin‐(9‐39). Under normoglycaemic conditions, neither GLP‐1 nor liraglutide affected ACh relaxation in rat mesenteric arteries. In arteries exposed to 40 mM glucose, GLP‐1, in contrast to liraglutide, potentiated ACh‐induced relaxation by a mechanism that was not antagonized by exendin‐(9‐39). GLP‐1 decreased superoxide levels measured with dihydroethidium in rat mesenteric arteries exposed to 40 mM glucose. Conclusions and Implications GLP‐1 receptors are involved in the liraglutide‐induced relaxation of branched arteries, under normoglycaemic conditions, while GLP‐1 inhibition of vascular superoxide levels contributes to GLP‐1 receptor‐independent potentiation of endothelium‐dependent vasodilatation in hyperglycaemia.

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Section: Discussionmentioning

confidence: 97%

Section: Introductionmentioning

confidence: 99%

Different mechanisms involved in liraglutide and glucagon‐like peptide‐1 vasodilatation in rat mesenteric small arteries

Bangshaab

Gutiérrez

Huynh

et al. 2018

British J Pharmacology

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“…DPP4i was reported to inhibit iNOS activity and iNOS-dependent NO production in a GLP-1 receptor dependent way in an LPS-septic model. The same study showed an inhibition of the NOX2isoform of NAPDH oxidase, with attenuation of ROS generation (24). DPP4i proved to reduce the inflammatory reaction by attenuation of the NF-κB p65 nuclear translocation and reduction of the release of inflammatory cytokines.…”

Section: Oxidative Stressmentioning

confidence: 71%

“…DPP4i reduces ROS production by NADPH oxidase production through the GLP-1/cAMP/PKA pathway in LPS-models (21,23,24). As NAPDPH oxidase plays © Annals of Translational Medicine.…”

Section: Discussionmentioning

confidence: 99%

Lung ischemia reperfusion injury: the therapeutic role of dipeptidyl peptidase 4 inhibition

et al. 2017

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Dipeptidyl peptidase 4 (DPP4) is a cell surface protease that has been reported to play a role in glucose homeostasis, cancer, HIV, autoimmunity, immunology and inflammation. A role for DPP4 in ischemia-reperfusion injury (IRI) in the heart has been established. Dipeptidyl peptidase 4 inhibition (DPP4i) appeared to decrease infarct size, improves cardiac function and promotes myocardial regeneration. Lung ischemia reperfusion injury is caused by a complex mechanism in which macrophages and neutrophils play an important role. Generation of reactive oxygen species (ROS), uncoupling of nitric oxide synthase (NOS), activation of nuclear factor-κB (NF-κB), activation of nicotinamide adenine dinucleotide phosphate metabolism, and generation of pro-inflammatory cytokines lead to acute lung injury (ALI). In this review we present the current knowledge on DPP4 as a target to treat IRI in the lung. We also provide evidence of the roles of the DPP4 substrates glucagon-like peptide 1 (GLP-1), vasoactive intestinal peptide (VIP) and stromal cell-derived factor-1α (SDF-1α) in protection against oxidative stress through activation of the mitogen-activated protein kinase (MAPK) 1/2 and phosphatidylinositol 3'-kinase (PI3K)/ Akt signal transduction pathways.Keywords: Acute lung injury (ALI); dipeptidyl peptidase 4 (DPP4); ischemia reperfusion injury; lung transplantation; reactive oxygen species (ROS)

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“…The authors also provide an overview on the techniques used to measure endothelial dysfunction and on antioxidant strategies applied to prevent endothelial dysfunction and improve the associated cardiovascular diseases. Steven et al () show that glucagon‐like peptide‐1 supplementation and dipeptidyl peptidase‐4 inhibition (both new generation antidiabetic drugs) induce glucose‐independent anti‐inflammatory, antioxidant and anti‐thrombotic effects in mice with experimental sepsis. Xia et al .…”

mentioning

confidence: 99%

Pharmacology of oxidative stress: translational opportunities

Daiber

Lisa

Ferdinándy

2017

British J Pharmacology

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Glucagon‐like peptide‐1 receptor signalling reduces microvascular thrombosis, nitro‐oxidative stress and platelet activation in endotoxaemic mice

Abstract: 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.

Cited by 72 publications

References 51 publications

Different mechanisms involved in liraglutide and glucagon‐like peptide‐1 vasodilatation in rat mesenteric small arteries

Different mechanisms involved in liraglutide and glucagon‐like peptide‐1 vasodilatation in rat mesenteric small arteries

Lung ischemia reperfusion injury: the therapeutic role of dipeptidyl peptidase 4 inhibition

Pharmacology of oxidative stress: translational opportunities

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