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Basic Res Cardiol (2015) 110:6 DOI 10.1007/s00395-015-0465-x
ORIGINAL CONTRIBUTION
Gliptin and GLP-1 analog treatment improves survival and vascular inammation/dysfunction in animalswith lipopolysaccharide-induced endotoxemia
Sebastian Steven Michael Hausding Swenja Krller-Schn Michael Mader Yuliya Mikhed
Paul Stamm Elena Zinius Amanda Pfeffer Philipp Welschof Saule Agdauletova Stephan Sudowe
Huige Li Matthias Oelze Eberhard Schulz Thomas Klein Thomas Mnzel Andreas Daiber
Received: 10 September 2014 / Revised: 22 December 2014 / Accepted: 9 January 2015 / Published online: 20 January 2015 Springer-Verlag Berlin Heidelberg 2015
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-inammatory 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 lg/kg/day). Endotoxic shock was induced by LPS injection (mice 17.520 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 inammatory parameters such as whole blood nitrosyl-iron hemoglobin (leukocyte-inducible nitric oxide synthase activity) or aortic mRNA expression of markers of inammation 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 benecial effects of linagliptin on vascular function and inammatory 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 inammatory complications in diabetic individuals
S. Steven and M. Hausding contributed equally to this study and should therefore both be considered as rst author.
Electronic supplementary material The online version of this article (doi:http://dx.doi.org/10.1007/s00395-015-0465-x
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S. Steven M. Hausding S. Krller-Schn M. Mader
Y. Mikhed P. Stamm E. Zinius A. Pfeffer P. Welschof
S. Agdauletova M....