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01.03.2015 | Original Contribution

Gliptin and GLP‐1 analog treatment improves survival and vascular inflammation/dysfunction in animals with lipopolysaccharide‐induced endotoxemia

verfasst von: Sebastian Steven, Michael Hausding, Swenja Kröller-Schön, Michael Mader, Yuliya Mikhed, Paul Stamm, Elena Zinßius, Amanda Pfeffer, Philipp Welschof, Saule Agdauletova, Stephan Sudowe, Huige Li, Matthias Oelze, Eberhard Schulz, Thomas Klein, Thomas Münzel, Andreas Daiber

Erschienen in: Basic Research in Cardiology | Ausgabe 2/2015

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Abstract

Dipeptidyl peptidase (DPP)-4 inhibitors are used to treat hyperglycemia by increasing the incretin glucagon-like peptide-1 (GLP-1). Previous studies showed anti-inflammatory and antiatherosclerotic effects of DPP-4 inhibitors. Here, we compared the effects of linagliptin versus sitagliptin and liraglutide on survival and vascular function in animal models of endotoxic shock by prophylactic therapy and treatment after lipopolysaccharide (LPS) injection. Gliptins were administered either orally or subcutaneously: linagliptin (5 mg/kg/day), sitagliptin (50 mg/kg/day) or liraglutide (200 µg/kg/day). Endotoxic shock was induced by LPS injection (mice 17.5–20 mg/kg i.p., rats 10 mg/kg/day). Linagliptin and liraglutide treatment or DPP-4 knockout improved the survival of endotoxemic mice, while sitagliptin was ineffective. Linagliptin, liraglutide and sitagliptin ameliorated LPS-induced hypotension and vascular dysfunction in endotoxemic rats, suppressed inflammatory parameters such as whole blood nitrosyl-iron hemoglobin (leukocyte-inducible nitric oxide synthase activity) or aortic mRNA expression of markers of inflammation as well as whole blood and aortic reactive oxygen species formation. Hemostasis (tail bleeding time, activated partial thromboplastin time) was impaired in endotoxemic rats and recovered under cotreatment with linagliptin and liraglutide. Finally, the beneficial effects of linagliptin on vascular function and inflammatory parameters in endotoxemic mice were impaired in AMP-activated kinase (alpha1) knockout mice. The improved survival of endotoxemic animals and other data shown here may warrant further clinical evaluation of these drugs in patients with septic shock beyond the potential improvement of inflammatory complications in diabetic individuals with special emphasis on the role of AMP-activated kinase (alpha1) in the DPP-4/GLP-1 cascade.

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Titel: Gliptin and GLP‐1 analog treatment improves survival and vascular inflammation/dysfunction in animals with lipopolysaccharide‐induced endotoxemia
verfasst von: Sebastian Steven
Michael Hausding
Swenja Kröller-Schön
Michael Mader
Yuliya Mikhed
Paul Stamm
Elena Zinßius
Amanda Pfeffer
Philipp Welschof
Saule Agdauletova
Stephan Sudowe
Huige Li
Matthias Oelze
Eberhard Schulz
Thomas Klein
Thomas Münzel
Andreas Daiber
Publikationsdatum: 01.03.2015
Verlag: Springer Berlin Heidelberg
Erschienen in: Basic Research in Cardiology / Ausgabe 2/2015
Print ISSN: 0300-8428
Elektronische ISSN: 1435-1803
DOI: https://doi.org/10.1007/s00395-015-0465-x

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Gliptin and GLP‐1 analog treatment improves survival and vascular inflammation/dysfunction in animals with lipopolysaccharide‐induced endotoxemia

Abstract

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